Anti-Tumor Immune Responses

Topic Information

Dear Colleagues,

It remains unclear how and when, during multi-step tumor progression via clonal selection, cancer cells are selected for their high mutational burden, as well as how the immune system is first alerted to their presence and begins its initial, often unsuccessful, attempts at eliminating them. At present, it is impossible to say which of the dozens of immunotherapy strategies under development will become the precursors of anti-cancer treatments that will prove to be vastly more effective than those developed to date and that will generate robust, durable responses for the majority of patients receiving treatment. For example, advances in molecular genetics, biochemistry, virus biology, cellular and system biology, and cellular immunology have recently converged with discoveries in drugs and antibodies to generate novel, potentially powerful ways to harness the immune response to eradicate human tumors. At this time, the action of the immune system has improved two types of attacks against infectious agents or cells targeted for destruction or neutralization. These involve humoral and cellular immunity, as some types of cells, particularly macrophages and NK cells, have an innate ability to recognize cells that should be destroyed. In this issue, we would like to discuss the frontiers in this area of research concerning cancer cell types where these phenomena have been proven to be positively active at the level of hematopoietic malignancies and, most importantly, in solid tumors with advanced immune therapies. Examples of instances where these strategies fail are of great value for better understanding how cancer cells evade this immune mechanism using the most recent genome biology technologies to determine which other genes/proteins/pathways are involved in these coordinated, interconnecting actions.

Prof. Dr. Massimo Zollo
Prof. Dr. Erle S. Robertson
Dr. Renata Grifantini
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Antibodies antibodies	3.0	7.1	2012	23 Days	CHF 1800
Cancers cancers	4.5	8.0	2009	16.3 Days	CHF 2900
Immuno immuno	2.1	2.6	2021	28.1 Days	CHF 1000
International Journal of Molecular Sciences ijms	4.9	8.1	2000	18.1 Days	CHF 2900
Vaccines vaccines	5.2	8.9	2013	17.6 Days	CHF 2700

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Open AccessArticle

Immune-Activated B Cells Are Dominant in Prostate Cancer

by Aws Saudi, Viqar Banday, A. Ali Zirakzadeh, Martin Selinger, Jon Forsberg, Martin Holmbom, Johan Henriksson, Mauritz Waldén, Farhood Alamdari, Firas Aljabery, Ola Winqvist and Amir Sherif

Cancers 2023, 15(3), 920; https://doi.org/10.3390/cancers15030920 - 1 Feb 2023

Cited by 8 | Viewed by 2956

Abstract

B cells are multifaceted immune cells responding robustly during immune surveillance against tumor antigens by presentation to T cells and switched immunoglobulin production. However, B cells are unstudied in prostate cancer (PCa). We used flow cytometry to analyze B-cell subpopulations in peripheral blood [...] Read more.

B cells are multifaceted immune cells responding robustly during immune surveillance against tumor antigens by presentation to T cells and switched immunoglobulin production. However, B cells are unstudied in prostate cancer (PCa). We used flow cytometry to analyze B-cell subpopulations in peripheral blood and lymph nodes from intermediate–high risk PCa patients. B-cell subpopulations were related to clinicopathological factors. B-cell-receptor single-cell sequencing and VDJ analysis identified clonal B-cell expansion in blood and lymph nodes. Pathological staging was pT2 in 16%, pT3a in 48%, and pT3b in 36%. Lymph node metastases occurred in 5/25 patients (20%). Compared to healthy donors, the peripheral blood CD19⁺ B-cell compartment was significantly decreased in PCa patients and dominated by naïve B cells. The nodal B-cell compartment had significantly increased fractions of CD19⁺ B cells and switched memory B cells. Plasmablasts were observed in tumor-draining sentinel lymph nodes (SNs). VDJ analysis revealed clonal expansion in lymph nodes. Thus, activated B cells are increased in SNs from PCa patients. The increased fraction of switched memory cells and plasmablasts together with the presence of clonally expanded B cells indicate tumor-specific T-cell-dependent responses from B cells, supporting an important role for B cells in the protection against tumors. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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15 pages, 1577 KiB  

Open AccessArticle

Tumor Response, Disease Control, and Progression-Free Survival as Surrogate Endpoints in Trials Evaluating Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: Study- and Patient-Level Analyses

by Nobuyuki Horita

Cancers 2023, 15(1), 185; https://doi.org/10.3390/cancers15010185 - 28 Dec 2022

Viewed by 1845

Abstract

Background: To assess the usefulness of tumor response and progression-free survival (PFS) as surrogates for overall survival (OS) in non-small cell lung cancer (NSCLC) trials with immune checkpoint inhibitors (ICI), which have not been confirmed. Methods: Patient- and trial-level analyses were [...] Read more.

Background: To assess the usefulness of tumor response and progression-free survival (PFS) as surrogates for overall survival (OS) in non-small cell lung cancer (NSCLC) trials with immune checkpoint inhibitors (ICI), which have not been confirmed. Methods: Patient- and trial-level analyses were performed. The Response Evaluation Criteria in Solid Tumors was preferred for image assessment. For trial-level analysis, surrogacy was assessed using the weighted rank correlation coefficient (r) following “reciprocal duplication.” This method duplicates all plots as if the experimental and the reference arms were switched. Monte Carlo simulations were performed for evaluating this method. Results: A total of 3312 cases were included in the patient-level analysis. Patients without response (first line (1L): hazard ratio (HR) 1.95, 95% confidence interval (CI) 1.71–2.23; second or later line (2L-): HR 4.22, 95% CI 3.22–5.53), without disease control (1L: HR 4.34, 95% CI 3.82–4.94; 2L-: HR 3.36, 95% CI 2.96–3.81), or with progression during the first year (1L: HR 3.42, 95% CI 2.60–4.50; 2L-: HR 3.33, 95% CI 2.64–4.20), had a higher risk of death. Systematic searches identified 38 RCTs including 17,515 patients for the study-level analysis. Odds ratio in the objective response rate (N = 38 × 2, r = −0.87) and HR in PFS (N = 38 × 2, r = 0.85) showed an excellent association with HR in overall survival, while this effect was not observed in the disease control rate (N = 26 × 2, r = −0.03). Conclusions: Objective response rate and PFS are reasonable surrogates for OS in NSCLC trials with ICI. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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19 pages, 1414 KiB  

Open AccessReview

Tertiary Lymphoid Structures: A Potential Biomarker for Anti-Cancer Therapy

by Ji’an Zou, Yingzhe Zhang, Yue Zeng, Yurong Peng, Junqi Liu, Chaoyue Xiao and Fang Wu

Cancers 2022, 14(23), 5968; https://doi.org/10.3390/cancers14235968 - 2 Dec 2022

Cited by 7 | Viewed by 3847

Abstract

A tertiary lymphoid structure (TLS) is a special component in the immune microenvironment that is mainly composed of tumor-infiltrating lymphocytes (TILs), including T cells, B cells, DC cells, and high endothelial venules (HEVs). For cancer patients, evaluation of the immune microenvironment has a [...] Read more.

A tertiary lymphoid structure (TLS) is a special component in the immune microenvironment that is mainly composed of tumor-infiltrating lymphocytes (TILs), including T cells, B cells, DC cells, and high endothelial venules (HEVs). For cancer patients, evaluation of the immune microenvironment has a predictive effect on tumor biological behavior, treatment methods, and prognosis. As a result, TLSs have begun to attract the attention of researchers as a new potential biomarker. However, the composition and mechanisms of TLSs are still unclear, and clinical detection methods are still being explored. Although some meaningful results have been obtained in clinical trials, there is still a long way to go before such methods can be applied in clinical practice. However, we believe that with the continuous progress of basic research and clinical trials, TLS detection and related treatment can benefit more and more patients. In this review, we generalize the definition and composition of TLSs, summarize clinical trials involving TLSs according to treatment methods, and describe possible methods of inducing TLS formation. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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16 pages, 719 KiB  

Open AccessReview

Current Developments in Cellular Therapy for Castration Resistant Prostate Cancer: A Systematic Review of Clinical Studies

by Christina Steinbach, Almas Merchant, Alexandru-Teodor Zaharie, Peter Horak, Maximilian Marhold and Michael Krainer

Cancers 2022, 14(22), 5719; https://doi.org/10.3390/cancers14225719 - 21 Nov 2022

Cited by 2 | Viewed by 2145

Abstract

Recently, the development of immunotherapies such as cellular therapy, monoclonal antibodies, vaccines and immunomodulators has revolutionized the treatment of various cancer entities. In order to close the existing gaps in knowledge about cellular immunotherapy, specifically focusing on the chimeric antigen receptors (CAR) T-cells, [...] Read more.

Recently, the development of immunotherapies such as cellular therapy, monoclonal antibodies, vaccines and immunomodulators has revolutionized the treatment of various cancer entities. In order to close the existing gaps in knowledge about cellular immunotherapy, specifically focusing on the chimeric antigen receptors (CAR) T-cells, their benefits and application in clinical settings, we conducted a comprehensive systematic review. Two co-authors independently searched the literature and characterized the results. Out of 183 records, 26 were considered eligible. This review provides an overview of the cellular immunotherapy landscape in treating prostate cancer, honing in on the challenges of employing CAR T-cell therapy. CAR T-cell therapy is a promising avenue for research due to the presence of an array of different tumor specific antigens. In prostate cancer, the complex microenvironment of the tumor vastly contributes to the success or failure of immunotherapies. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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20 pages, 7689 KiB  

Open AccessArticle

Beta-Glucan from S. cerevisiae Protected AOM-Induced Colon Cancer in cGAS-Deficient Mice Partly through Dectin-1-Manipulated Macrophage Cell Energy

by Sulaiman Binmama, Cong Phi Dang, Peerapat Visitchanakun, Pratsanee Hiengrach, Naraporn Somboonna, Thanya Cheibchalard, Prapaporn Pisitkun, Ariya Chindamporn and Asada Leelahavanichkul

Int. J. Mol. Sci. 2022, 23(18), 10951; https://doi.org/10.3390/ijms231810951 - 19 Sep 2022

Cited by 11 | Viewed by 3276

Abstract

Although the impacts of Saccharomyces cerevisiae on cancers are mentioned, data on its use in mice with cyclic GMP-AMP synthase deficiency (cGAS-/-) are even rarer. Here, 12 weeks of oral administration of S. cerevisiae protected cGAS-/- mice from azoxymethane (AOM)-induced colon cancers, partly [...] Read more.

Although the impacts of Saccharomyces cerevisiae on cancers are mentioned, data on its use in mice with cyclic GMP-AMP synthase deficiency (cGAS-/-) are even rarer. Here, 12 weeks of oral administration of S. cerevisiae protected cGAS-/- mice from azoxymethane (AOM)-induced colon cancers, partly through dysbiosis attenuation (fecal microbiome analysis). In parallel, a daily intralesional injection of a whole glucan particle (WGP; the beta-glucan extracted from S. cerevisiae) attenuated the growth of subcutaneous tumor using MC38 (murine colon cancer cell line) in cGAS-/- mice. Interestingly, the incubation of fluorescent-stained MC38 with several subtypes of macrophages, including M1 (using Lipopolysaccharide; LPS), M2 (IL-4), and tumor-associated macrophages (TAM; using MC38 supernatant activation), could not further reduce the tumor burdens (fluorescent intensity) compared with M0 (control culture media). However, WGP enhanced tumoricidal activities (fluorescent intensity), the genes of M1 pro-inflammatory macrophage polarization (IL-1β and iNOS), and Dectin-1 expression and increased cell energy status (extracellular flux analysis) in M0, M2, and TAM. In M1, WGP could not increase tumoricidal activities, Dectin-1, and glycolysis activity, despite the upregulated IL-1β. In conclusion, S. cerevisiae inhibited the growth of colon cancers through dysbiosis attenuation and macrophage energy activation, partly through Dectin-1 stimulation. Our data support the use of S. cerevisiae for colon cancer protection. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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9 pages, 772 KiB  

Open AccessArticle

Inefficient Induction of Neutralizing Antibodies against SARS-CoV-2 Variants in Patients with Inflammatory Bowel Disease on Anti-Tumor Necrosis Factor Therapy after Receiving a Third mRNA Vaccine Dose

by Paola López-Marte, Alondra Soto-González, Lizzie Ramos-Tollinchi, Stephan Torres-Jorge, Mariana Ferre, Esteban Rodríguez-Martinó, Esther A. Torres and Carlos A. Sariol

Vaccines 2022, 10(8), 1301; https://doi.org/10.3390/vaccines10081301 - 11 Aug 2022

Cited by 4 | Viewed by 2440

Abstract

Management of inflammatory bowel disease (IBD) often relies on biological and immunomodulatory agents for remission through immunosuppression, raising concerns regarding the SARS-CoV-2 vaccine’s effectiveness. The emergent variants have hindered the vaccine neutralization capacity, and whether the third vaccine dose can neutralize SARS-CoV-2 variants [...] Read more.

Management of inflammatory bowel disease (IBD) often relies on biological and immunomodulatory agents for remission through immunosuppression, raising concerns regarding the SARS-CoV-2 vaccine’s effectiveness. The emergent variants have hindered the vaccine neutralization capacity, and whether the third vaccine dose can neutralize SARS-CoV-2 variants in this population remains unknown. This study aims to evaluate the humoral response of SARS-CoV-2 variants in patients with IBD 60 days after the third vaccine dose [BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna)]. Fifty-six subjects with IBD and 12 healthy subjects were recruited. Ninety percent of patients with IBD (49/56) received biologics and/or immunomodulatory therapy. Twenty-four subjects with IBD did not develop effective neutralizing capability against the Omicron variant. Seventy percent (17/24) of those subjects received anti-tumor necrosis factor therapy [10 = adalimumab, 7 = infliximab], two of which had a history of COVID-19 infection, and one subject did not develop immune neutralization against three other variants: Gamma, Epsilon, and Kappa. All subjects in the control group developed detectable antibodies and effective neutralization against all seven SARS-CoV-2 variants. Our study shows that patients with IBD might not be protected against SARS-CoV-2 variants, and more extensive studies are needed to evaluate optimal immunity. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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27 pages, 6028 KiB  

Open AccessArticle

Systematic Identification of the RNA-Binding Protein STAU2 as a Key Regulator of Pancreatic Adenocarcinoma

by Xiao Wang, Wenbin Kuang, Jiayu Ding, Jiaxing Li, Minghui Ji, Weijiao Chen, Hao Shen, Zhongrui Shi, Dawei Wang, Liping Wang and Peng Yang

Cancers 2022, 14(15), 3629; https://doi.org/10.3390/cancers14153629 - 26 Jul 2022

Cited by 5 | Viewed by 3424

Abstract

Pancreatic adenocarcinoma (PAAD) is a highly aggressive cancer. RNA-binding proteins (RBPs) regulate highly dynamic post-transcriptional processes and perform very important biological functions. Although over 1900 RBPs have been identified, most are considered markers of tumor progression, and further information on their general role [...] Read more.

Pancreatic adenocarcinoma (PAAD) is a highly aggressive cancer. RNA-binding proteins (RBPs) regulate highly dynamic post-transcriptional processes and perform very important biological functions. Although over 1900 RBPs have been identified, most are considered markers of tumor progression, and further information on their general role in PAAD is not known. Here, we report a bioinformatics analysis that identified five hub RBPs and produced a high-value prognostic model based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Among these, the prognostic signature of the double-stranded RNA binding protein Staufen double-stranded RNA (STAU2) was identified. Firstly, we found that it is a highly expressed critical regulator of PAAD associated with poor clinical outcomes. Accordingly, the knockdown of STAU2 led to a profound decrease in PAAD cell growth, migration, and invasion and induced apoptosis of PAAD cells. Furthermore, through multiple omics analyses, we identified the key target genes of STAU2: Palladin cytoskeletal associated protein (PALLD), Heterogeneous nuclear ribonucleoprotein U (HNRNPU), SERPINE1 mRNA Binding Protein 1 (SERBP1), and DEAD-box polypeptide 3, X-Linked (DDX3X). Finally, we found that a high expression level of STAU2 not only helps PAAD evade the immune response but is also related to chemotherapy drug sensitivity, which implies that STAU2 could serve as a potential target for combinatorial therapy. These findings uncovered a novel role for STAU2 in PAAD aggression and resistance, suggesting that it probably represents a novel therapeutic and drug development target. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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13 pages, 3353 KiB  

Open AccessArticle

Tumor-Stroma Ratio and Programmed Cell Death Ligand 1 Expression in Preoperative Biopsy and Matched Laryngeal Carcinoma Surgical Specimen

by Lara Alessandrini, Leonardo Franz, Marta Sbaraglia, Tommaso Saccardo, Filippo Cappello, Alessandro Drigo, Anna Chiara Frigo and Gino Marioni

Int. J. Mol. Sci. 2022, 23(14), 8053; https://doi.org/10.3390/ijms23148053 - 21 Jul 2022

Cited by 6 | Viewed by 2168

Abstract

Programmed cell death ligand 1 (PD-L1) seems to rely on close relations between neoplastic and immune cells in the tumor microenvironment. Tumor to stroma ratio (TSR) has been associated with prognosis in different malignancies. The aims of this exploratory investigation were to analyze [...] Read more.

Programmed cell death ligand 1 (PD-L1) seems to rely on close relations between neoplastic and immune cells in the tumor microenvironment. Tumor to stroma ratio (TSR) has been associated with prognosis in different malignancies. The aims of this exploratory investigation were to analyze for the first time the: (i) association between TSR, PD-L1 expression and other clinical–pathological features in laryngeal squamous cell carcinoma (LSCC) biopsies and paired surgical specimens; (ii) prognostic and predictive role of TSR and PD-L1. TSR, PD-L1 expression (in terms of combined positive score [CPS]), and other clinical–pathological features were analyzed in biopsies and surgical specimens of 43 consecutive LSCC cases. A CPS < 1 evaluated on surgical specimens was associated with a low TSR (stroma rich) on both biopsies and surgical specimens (p = 0.0143 and p = 0.0063). Low TSR showed a significant negative prognostic value when evaluated on both biopsies and surgical specimens (HR = 8.808, p = 0.0003 and HR = 11.207, p = 0.0002). CPS ≥ 1 appeared to be a favorable prognostic factor (HR = 0.100, p = 0.0265). The association between bioptic and surgical specimen TSR and PD-L1 expression should be further investigated for a potential impact on targeted treatments, also with regard to immunotherapeutic protocols. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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11 pages, 1623 KiB  

Open AccessArticle

Stability Program in Dendritic Cell Vaccines: A “Real-World” Experience in the Immuno-Gene Therapy Factory of Romagna Cancer Center

by Elena Pancisi, Anna Maria Granato, Emanuela Scarpi, Laura Ridolfi, Silvia Carloni, Cinzia Moretti, Massimo Guidoboni, Francesco De Rosa, Sara Pignatta, Claudia Piccinini, Valentina Soldati, Luana Calabrò, Massimo Framarini, Monica Stefanelli, Jenny Bulgarelli, Marcella Tazzari, Francesca Fanini and Massimiliano Petrini

Vaccines 2022, 10(7), 999; https://doi.org/10.3390/vaccines10070999 - 23 Jun 2022

Cited by 4 | Viewed by 2674

Abstract

Advanced therapy medical products (ATMPs) are rapidly growing as innovative medicines for the treatment of several diseases. Hence, the role of quality analytical tests to ensure consistent product safety and quality has become highly relevant. Several clinical trials involving dendritic cell (DC)-based vaccines [...] Read more.

Advanced therapy medical products (ATMPs) are rapidly growing as innovative medicines for the treatment of several diseases. Hence, the role of quality analytical tests to ensure consistent product safety and quality has become highly relevant. Several clinical trials involving dendritic cell (DC)-based vaccines for cancer treatment are ongoing at our institute. The DC-based vaccine is prepared via CD14+ monocyte differentiation. A fresh dose of 10 million DCs is administered to the patient, while the remaining DCs are aliquoted, frozen, and stored in nitrogen vapor for subsequent treatment doses. To evaluate the maintenance of quality parameters and to establish a shelf life of frozen vaccine aliquots, a stability program was developed. Several parameters of the DC final product at 0, 6, 12, 18, and 24 months were evaluated. Our results reveal that after 24 months of storage in nitrogen vapor, the cell viability is in a range between 82% and 99%, the expression of maturation markers remains inside the criteria for batch release, the sterility tests are compliant, and the cell costimulatory capacity unchanged. Thus, the data collected demonstrate that freezing and thawing do not perturb the DC vaccine product maintaining over time its functional and quality characteristics. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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20 pages, 1902 KiB  

Open AccessReview

Microbial-Derived Toll-like Receptor Agonism in Cancer Treatment and Progression

by Eileena F. Giurini, Mary Beth Madonna, Andrew Zloza and Kajal H. Gupta

Cancers 2022, 14(12), 2923; https://doi.org/10.3390/cancers14122923 - 14 Jun 2022

Cited by 9 | Viewed by 4742

Abstract

Toll-like receptors (TLRs) are typical transmembrane proteins, which are essential pattern recognition receptors in mediating the effects of innate immunity. TLRs recognize structurally conserved molecules derived from microbes and damage-associated molecular pattern molecules that play an important role in inflammation. Since the first [...] Read more.

Toll-like receptors (TLRs) are typical transmembrane proteins, which are essential pattern recognition receptors in mediating the effects of innate immunity. TLRs recognize structurally conserved molecules derived from microbes and damage-associated molecular pattern molecules that play an important role in inflammation. Since the first discovery of the Toll receptor by the team of J. Hoffmann in 1996, in Drosophila melanogaster, numerous TLRs have been identified across a wide range of invertebrate and vertebrate species. TLR stimulation leads to NF-κB activation and the subsequent production of pro-inflammatory cytokines and chemokines, growth factors and anti-apoptotic proteins. The expression of TLRs has also been observed in many tumors, and their stimulation results in tumor progression or regression, depending on the TLR and tumor type. The anti-tumoral effects can result from the activation of anti-tumoral immune responses and/or the direct induction of tumor cell death. The pro-tumoral effects may be due to inducing tumor cell survival and proliferation or by acting on suppressive or inflammatory immune cells in the tumor microenvironment. The aim of this review is to draw attention to the effects of TLR stimulation in cancer, the activation of various TLRs by microbes in different types of tumors, and, finally, the role of TLRs in anti-cancer immunity and tumor rejection. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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15 pages, 7069 KiB  

Open AccessArticle

A Fraction of CD8+ T Cells from Colorectal Liver Metastases Preferentially Repopulate Autologous Patient-Derived Xenograft Tumors as Tissue-Resident Memory T Cells

by Frank Liang, Lisa M. Nilsson, Fabian Byvald, Azar Rezapour, Helena Taflin, Jonas A. Nilsson and Ulf Yrlid

Cancers 2022, 14(12), 2882; https://doi.org/10.3390/cancers14122882 - 10 Jun 2022

Cited by 7 | Viewed by 3839

Abstract

The diversity of T cells in the human liver may reflect the composition of TILs in CRLM. Our ex vivo characterization of CRLM vs. adjacent liver tissue detected CD103+CD39+CD8+ T_RM cells predominantly in CRLM, which prompted further assessments. These T_RM cells [...] Read more.

The diversity of T cells in the human liver may reflect the composition of TILs in CRLM. Our ex vivo characterization of CRLM vs. adjacent liver tissue detected CD103+CD39+CD8+ T_RM cells predominantly in CRLM, which prompted further assessments. These T_RM cells responded to cognate antigens in vitro. As functional activities of autologous TILs are central to the implementation of personalized cancer treatments, we applied a patient-derived xenograft (PDX) model to monitor TILs’ capacity to control CRLM-derived tumors in vivo. We established PDX mice with CRLMs from two patients, and in vitro expansion of their respective TILs resulted in opposing CD4+ vs. CD8+ TIL ratios. These CRLMs also displayed mutated KRAS, which enabled trametinib-mediated inhibition of MEK. Regardless of the TIL subset ratio, persistent or transient control of CRLM-derived tumors of limited size by the transferred TILs was observed only after trametinib treatment. Of note, a portion of transferred TILs was observed as CD103+CD8+ T_RM cells that strictly accumulated within the autologous CRLM-derived tumor rather than in the spleen or blood. Thus, the predominance of CD103+CD39+CD8+ T_RM cells in CRLM relative to the adjacent liver and the propensity of CD103+CD8+ T_RM cells to repopulate the autologous tumor may identify these TILs as strategic targets for therapies against advanced CRC. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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Open AccessArticle

Photodynamic Therapy in Combination with the Hepatitis B Core Virus-like Particles (HBc VLPs) to Prime Anticancer Immunity for Colorectal Cancer Treatment

by Yang Hao, Zili Gu, Zhenfeng Yu, Timo Schomann, Sana Sayedipour, Julio C. Aguilar, Peter ten Dijke and Luis J. Cruz

Cancers 2022, 14(11), 2724; https://doi.org/10.3390/cancers14112724 - 31 May 2022

Cited by 13 | Viewed by 3603

Abstract

Photodynamic therapy (PDT), which combines light and oxygen with a photosensitizer to induce reactive oxygen species (ROS)-mediated killing of primary tumor cells, benefits from non-invasive properties and its negligible toxicity to surrounding healthy tissues. In this study, we have shown that the second-generation [...] Read more.

Photodynamic therapy (PDT), which combines light and oxygen with a photosensitizer to induce reactive oxygen species (ROS)-mediated killing of primary tumor cells, benefits from non-invasive properties and its negligible toxicity to surrounding healthy tissues. In this study, we have shown that the second-generation photosensitizer FOSCAN can be internalized by tumor cells and effectively induce tumor cell death when exposed to laser irradiation in vitro. In addition, these dying tumor cells can be phagocytosed by dendritic cells and lead to their activation and maturation as assessed by in vitro co-culture models. While PDT induces immunogenic tumor cell apoptosis, its application for the treatment of tumors located in deep tissues and advanced malignancies has been limited. In this study, we demonstrate that hepatitis B core virus-like particles (HBc VLPs) can serve as a vaccine to enhance PDT-induced anti-cancer immunity by priming humoral immune responses and inducing CD8⁺ T cell responses. The combination of PDT and HBc VLPs increased the survival rate of MC-38 tumor-bearing mice to 55%, compared to 33% in PDT alone and no tumor-free mice in vaccine alone. Moreover, the combination effectively prevented tumor recurrence in vivo through enhanced immune memory T cells after therapy. Therefore, as both are clinically approved techniques, this combination provides a promising strategy for cancer therapy. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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15 pages, 4940 KiB  

Open AccessArticle

Combination of OX40 Co-Stimulation, Radiotherapy, and PD-1 Inhibition in a Syngeneic Murine Triple-Negative Breast Cancer Model

by Min Guk Han, Chan Woo Wee, Mi Hyun Kang, Min Ji Kim, Seung Hyuck Jeon and In Ah Kim

Cancers 2022, 14(11), 2692; https://doi.org/10.3390/cancers14112692 - 29 May 2022

Cited by 14 | Viewed by 3306

Abstract

Immune checkpoint inhibitors have been successful in a wide range of tumor types but still have limited efficacy in immunologically cold tumors, such as breast cancers. We hypothesized that the combination of agonistic anti-OX40 (α-OX40) co-stimulation, PD-1 blockade, and radiotherapy would improve the [...] Read more.

Immune checkpoint inhibitors have been successful in a wide range of tumor types but still have limited efficacy in immunologically cold tumors, such as breast cancers. We hypothesized that the combination of agonistic anti-OX40 (α-OX40) co-stimulation, PD-1 blockade, and radiotherapy would improve the therapeutic efficacy of the immune checkpoint blockade in a syngeneic murine triple-negative breast cancer model. Murine triple-negative breast cancer cells (4T1) were grown in immune-competent BALB/c mice, and tumors were irradiated with 24 Gy in three fractions. PD-1 blockade and α-OX40 were administered five times every other day. Flow cytometric analyses and immunohistochemistry were used to monitor subsequent changes in the immune cell repertoire. The combination of α-OX40, radiotherapy, and PD-1 blockade significantly improved primary tumor control, abscopal effects, and long-term survival beyond 2 months (60%). In the tumor microenvironment, the ratio of CD8+ T cells to CD4 + FOXP3+ regulatory T cells was significantly elevated and exhausted CD8+ T cells (PD-1+, CTLA-4+, TIM-3+, or LAG-3+ cells) were significantly reduced in the triple combination group. Systemically, α-OX40 co-stimulation and radiation significantly increased the CD103+ dendritic cell response in the spleen and plasma IFN-γ, respectively. Together, our results suggest that the combination of α-OX40 co-stimulation and radiation is a viable approach to overcome therapeutic resistance to PD-1 blockade in immunologically cold tumors, such as triple-negative breast cancer. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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13 pages, 3383 KiB  

Open AccessArticle

Acanthopanax senticosus Polysaccharide Enhances the Pathogen Resistance of Radiation-Damaged Caenorhabditis elegans through Intestinal p38 MAPK-SKN-1/ATF-7 Pathway and Stress Response

by Mengyao Liu, Nana Li, Shan Shan, Yudong Shi, Yuanbing Zhu and Weihong Lu

Int. J. Mol. Sci. 2022, 23(9), 5034; https://doi.org/10.3390/ijms23095034 - 1 May 2022

Cited by 5 | Viewed by 2637

Abstract

With the advancement of science and technology, humans are chronically exposed to ionizing radiation. It is crucial to look for efficient and low-toxic anti-radiation agents. Through preliminary screening, we found that Acanthopanax senticosus polysaccharide (ASPS) played a major role in regulating immune damage [...] Read more.

With the advancement of science and technology, humans are chronically exposed to ionizing radiation. It is crucial to look for efficient and low-toxic anti-radiation agents. Through preliminary screening, we found that Acanthopanax senticosus polysaccharide (ASPS) played a major role in regulating immune damage caused by radiation. The objective of this study was to apply the Caenorhabditis elegans—P. aeruginosa (PA14) infection model to illuminate the mechanism of ASPS increasing the pathogen resistance of radiation-damaged nematodes. Results indicated that ASPS (1 mg/mL) significantly enhanced the pathogen resistance of radiation-damaged nematodes by directly elevating the immune response of nematodes rather than by affecting the bacterial activity. Through further research on the p38 MAPK signaling pathway and related mutants, we found that ASPS functioned by the p38 MAPK pathway in the intestine, and SKN-1, ATF-7 as the downstream targets of PMK-1 participated the regulation of ASPS. In addition, ASPS markedly alleviated the stress status of damaged nematodes by regulating oxidative stress. Collectively, our findings suggest that ASPS enhances the pathogen resistance of radiation-damaged nematodes through the intestinal p38MAPK-SKN-1/ATF-7 pathway and stress response. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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16 pages, 2698 KiB  

Open AccessArticle

A Physiologically Based Pharmacokinetic Framework for Quantifying Antibody Distribution Gradients from Tumors to Tumor-Draining Lymph Nodes

by Eric Salgado and Yanguang Cao

Antibodies 2022, 11(2), 28; https://doi.org/10.3390/antib11020028 - 14 Apr 2022

Cited by 1 | Viewed by 3616

Abstract

Immune checkpoint blockades prescribed in the neoadjuvant setting are now under active investigation for many types of tumors, and many have shown early success. The primary tumor (PT) and tumor-draining lymph node (TDLN) immune factors, along with adequate therapeutic antibody distributions to the [...] Read more.

Immune checkpoint blockades prescribed in the neoadjuvant setting are now under active investigation for many types of tumors, and many have shown early success. The primary tumor (PT) and tumor-draining lymph node (TDLN) immune factors, along with adequate therapeutic antibody distributions to the PT and TDLN, are critical for optimal immune activation and anti-tumor efficacy in neoadjuvant immunotherapy. However, it remains largely unknown how much of the antibody can be distributed into the PT-TDLN axis at different clinical scenarios. The goal of the current work is to build a physiologically based pharmacokinetic (PBPK) model framework capable of characterizing antibody distribution gradients in the PT-TDLN axis across various clinical and pathophysiological scenarios. The model was calibrated using clinical data from immuno-PET antibody-imaging studies quantifying antibody pharmacokinetics (PK) in the blood, PTs, and TDLNs. The effects of metastatic lesion location, tumor-induced compression, and inflammation, as well as surgery, on antibody concentration gradients in the PT-TDLN axis were characterized. The PBPK model serves as a valuable tool to predict antibody exposures in various types of tumors, metastases, and the associated lymph node, supporting effective immunotherapy. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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16 pages, 1672 KiB  

Open AccessArticle

Outcomes and Toxicities of Modern Combined Modality Therapy with Atezolizumab Plus Bevacizumab and Radiation Therapy for Hepatocellular Carcinoma

by Gohar Shahwar Manzar, Brian Sandeep De, Chike Osita Abana, Sunyoung S. Lee, Milind Javle, Ahmed O. Kaseb, Jean-Nicolas Vauthey, Hop Sanderson Tran Cao, Albert C. Koong, Grace Li Smith, Cullen M. Taniguchi, Emma Brey Holliday, Prajnan Das, Eugene Jon Koay and Ethan Bernard Ludmir

Cancers 2022, 14(8), 1901; https://doi.org/10.3390/cancers14081901 - 9 Apr 2022

Cited by 20 | Viewed by 3753

Abstract

Atezolizumab plus bevacizumab has become frontline therapy for unresectable HCC. The compatibility of atezolizumab/bevacizumab with liver-directed RT has not been reported. Methods: HCC patients treated with liver-directed RT and atezolizumab/bevacizumab between 1/2020–11/2021 were included. Toxicity and outcomes were retrospectively recorded. For ALCs, we [...] Read more.

Atezolizumab plus bevacizumab has become frontline therapy for unresectable HCC. The compatibility of atezolizumab/bevacizumab with liver-directed RT has not been reported. Methods: HCC patients treated with liver-directed RT and atezolizumab/bevacizumab between 1/2020–11/2021 were included. Toxicity and outcomes were retrospectively recorded. For ALCs, we matched the analysis to a previously cohort of RT-treated HCC patients who did not receive atezolizumab/bevacizumab. Survival and time-to-liver-failure were analyzed using Kaplan–Meier. Results: Of 21 patients, with a median follow-up of 9.5 months, the median OS was 16.1 months. Post-RT, all patients had reduced tumors or treatment response. There were no ≥Grade 3 RT-related toxicities. Autoimmune complications occurred in two patients (9.5%), and GI bleeding in three patients (14.3%). Liver function remained stable post-RT. There was a marked decrease in ALCs immediately post-RT (post-RT/pre-RT ratio 47.3%, p < 0.0001), restored by 1 month to pre-treatment baseline (1-month post-RT/pre-RT ratio 95.1%, n.s.). Compared to HCC patients treated with RT alone, post-RT ALC recovery was faster with atezolizumab/bevacizumab (p = 0.009). Conclusion: In this first reported experience of RT with modern systemic therapy for HCC, combination therapy is safe and well-tolerated. As a favorable prognosticator, there appears to be faster recovery of ALC among patients who received RT with atezolizumab/bevacizumab. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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16 pages, 10548 KiB  

Open AccessArticle

Norcantharidin Induces Immunogenic Cell Death of Bladder Cancer Cells through Promoting Autophagy in Acidic Culture

by Lili Xu, Bijia Su, Lijun Mo, Chenye Zhao, Zhenlin Zhao, Hongwei Li, Zhiming Hu and Jinlong Li

Int. J. Mol. Sci. 2022, 23(7), 3944; https://doi.org/10.3390/ijms23073944 - 1 Apr 2022

Cited by 17 | Viewed by 2712

Abstract

The acidic tumor microenvironment stands as a major obstacle to the efficient elimination of tumor cells. Norcantharidin (NCTD) is a powerful antitumor agent with multiple bioactivities. However, the effect of NCTD under acidic conditions is still unclear. Here, we report that NCTD can [...] Read more.

The acidic tumor microenvironment stands as a major obstacle to the efficient elimination of tumor cells. Norcantharidin (NCTD) is a powerful antitumor agent with multiple bioactivities. However, the effect of NCTD under acidic conditions is still unclear. Here, we report that NCTD can efficiently kill bladder cancer (BC) cells in acidic culture, and more intriguingly, NCTD can induce immunogenic cell death (ICD), thereby promoting antitumor immunity. In NCTD-treated BC cells, the surface-exposed calreticulin (ecto-CALR) was significantly increased. Consistently, co-culture with these cells promoted dendritic cell (DC) maturation. The NCTD-induced ICD is autophagy dependent, as autophagy inhibition completely blocked the NCTD-induced ecto-CALR and DC maturation. In addition, the DC showed a distinct maturation phenotype (CD80^high CD86^low) in acidic culture, as compared to that in physiological pH (CD⁸⁰ high CD86^high). Finally, the NCTD-induced ICD was validated in a mouse model. NCTD treatment significantly increased the tumor-infiltrating T lymphocytes in MB49 bladder cancer mice. Immunizing mice with NCTD-treated MB49 cells significantly increased tumor-free survival as compared to control. These findings demonstrate that NCTD could induce ICD in an acidic environment and suggest the feasibility to combine NCTD with anticancer immunotherapy to treat BC. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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15 pages, 1299 KiB  

Open AccessEditor’s ChoiceArticle

Tumor Infiltration Levels of CD3, Foxp3 (+) Lymphocytes and CD68 Macrophages at Diagnosis Predict 5-Year Disease-Specific Survival in Patients with Oropharynx Squamous Cell Carcinoma

by Borghild Ljokjel, Hilde Haave, Stein Lybak, Olav Karsten Vintermyr, Lars Helgeland and Hans Jørgen Aarstad

Cancers 2022, 14(6), 1508; https://doi.org/10.3390/cancers14061508 - 15 Mar 2022

Cited by 11 | Viewed by 2611

Abstract

Head and neck cancer (HNC) is the sixth most common cancer worldwide. Oropharyngeal (OP) cancers are of special interest because of possible underlying HPV infection which is tied to prognosis. Influxes of inflammatory cells into tumors may vary with prognoses. We wanted to [...] Read more.

Head and neck cancer (HNC) is the sixth most common cancer worldwide. Oropharyngeal (OP) cancers are of special interest because of possible underlying HPV infection which is tied to prognosis. Influxes of inflammatory cells into tumors may vary with prognoses. We wanted to study whether the number of tumor-infiltrating lymphocytes (TIL) and tumor-associated macrophages (TAM) in tumors correlated to HPV status and predicted 5-year disease-specific survival (DSS). Formalin-fixed paraffin-embedded (FFPE) biopsies cut sections from 170 patients treated for OP cancer were stained by immunohistochemistry and evaluated for the number of CD68 (+) TAMs, CD3 (+), and Foxp3 (+) (T regulatory) TILs. From FFPE slides HPV by PCR and p16 by immunohistochemistry were established. From FFPE Hematoxylin-Eosin slides, levels of tumor nuclear polymorphism, tumor invasion, desmoplasia, and inflammation were determined as previously published. Levels of TIL CD3 (+) and TIL Foxp3 (+) were increased among the HPV (+) compared to the HPV (−) patients. High levels of TIL Foxp3 (+) and CD68 (+) macrophages predicted better 5-year DSS. TIL Foxp3 (+) levels predicted independent of age, gender, TNM stage, and HPV infection as well as level of stromal desmoplasia, tumor invasion, and nuclear polymorphism, but more pronounced among tumor HPV (+) than HPV (−) patients. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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10 pages, 612 KiB  

Open AccessArticle

Immune-Checkpoint Inhibitors for Malignant Pleural Mesothelioma: A French, Multicenter, Retrospective Real-World Study

by Jean-Baptiste Assié, Florian Crépin, Emmanuel Grolleau, Anthony Canellas, Margaux Geier, Aude Grébert-Manuardi, Nabila Akkache, Aldo Renault, Pierre-Alexandre Hauss, Marielle Sabatini, Valentine Bonnefoy, Alexis Cortot, Marie Wislez, Clément Gauvain, Christos Chouaïd, Arnaud Scherpereel and Isabelle Monnet

Cancers 2022, 14(6), 1498; https://doi.org/10.3390/cancers14061498 - 15 Mar 2022

Cited by 11 | Viewed by 2963

Abstract

Backgrounds: Malignant pleural mesothelioma (MPM) is a cancer with poor prognosis. Second-line and onward therapy has many options, including immune-checkpoint inhibitors with demonstrated efficacy: 10–25% objective response rate (ORR) and 40–70% disease-control rate (DCR) in clinical trials on selected patients. This study evaluated [...] Read more.

Backgrounds: Malignant pleural mesothelioma (MPM) is a cancer with poor prognosis. Second-line and onward therapy has many options, including immune-checkpoint inhibitors with demonstrated efficacy: 10–25% objective response rate (ORR) and 40–70% disease-control rate (DCR) in clinical trials on selected patients. This study evaluated real-life 2L+ nivolumab efficacy in MPM patients and looked for factors predictive of response. Methods: This retrospective study included (September 2017–July 2021) all MPM patients managed in 11 French centers. Results: The 109 enrolled patients’ characteristics were: median age: 69 years; 67.9% men; 82.6% epithelioid subtype. Strictly, second-line nivolumab was given to 51.4%. Median PFS and OS were 3.8 (3.2–5.9) and 12.8 (9.2–16.4) months. ORR was 17/109 (15.6%); 34/109 patients had a stabilized disease (DCR 46.8%). Univariable analysis identified several parameters as significantly (p < 0.05) prognostic of OS [HR (95% CI)]: biphasic subtype: 3.3 (1.52–7.0), intermediate Lung Immune Prognostic Index score: 0.46 (0.22–0.99), progression on the line preceding nivolumab: 2.1 (1.11–3.9) and age > 70 years: 2.5 (1.5–4.0). Multivariable analyses retained only biphasic subtype: 3.57 (1.08–11.8) and albumin < 25 g/L: 10.28 (1.5–70.7) as significant and independent predictors. Conclusions: Second-line and onward nivolumab is effective against MPM in real life but with less effectiveness in >70 years. Ancillary studies are needed to identify the predictive factors. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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22 pages, 5701 KiB  

Open AccessArticle

Design, Synthesis and Structure-Activity Relationship Studies of Meridianin Derivatives as Novel JAK/STAT3 Signaling Inhibitors

by Jian-Qiang Zhang, Rui Li, Xue-Yang Dong, Na He, Rui-Juan Yin, Meng-Ke Yang, Jie-Yu Liu, Ri-Lei Yu, Chen-Yang Zhao and Tao Jiang

Int. J. Mol. Sci. 2022, 23(4), 2199; https://doi.org/10.3390/ijms23042199 - 16 Feb 2022

Cited by 9 | Viewed by 2527

Abstract

Hyperactivation of Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling is an attractive therapeutic target for tumor therapy. Herein, forty-eight novel meridianin derivatives were designed and synthesized, and their antitumor activity was evaluated in vitro both for activity optimization and [...] Read more.

Hyperactivation of Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling is an attractive therapeutic target for tumor therapy. Herein, forty-eight novel meridianin derivatives were designed and synthesized, and their antitumor activity was evaluated in vitro both for activity optimization and structure–activity relationship (SAR) study. The results indicated that most derivatives exhibited significantly improved antitumor activity, especially for compound 6e. The compound 6e contains an isothiouronium linked by an alkyl chain consisting of six carbon atoms with IC₅₀ ranging from 1.11 to 2.80 μM on various cancer cell lines. Consistently, the 6e dose dependently induced the apoptosis of A549 and DU145 cells, in which STAT3 is constitutively active. Western blotting assays indicated that the phosphorylation levels of JAK1, JAK2 and STAT3 were inhibited by 6e at 5 μM without significant change in the total STAT3 level. Moreover, 6e also suppressed the expression of STAT3 downstream genes, including c-Myc, Cyclin D1 and Bcl-XL at 10 μM. An additional in vivo study revealed that 6e at the dose of 10 mg/kg could potently inhibit the DU145 xenograft tumor without obvious body weight loss. These results clearly indicate that 6e could be a potential antitumor agent by targeting the JAK/STAT3 signaling pathway. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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