Biomolecules

2024

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13 pages, 1862 KiB

Open AccessArticle

IFN-Type-I Response and Systemic Immunity in Rectal Adenocarcinoma Patients Treated with Conventional or Hypofractionated Neoadjuvant Radiotherapy

by Ioannis M. Koukourakis, Erasmia Xanthopoulou, Michael I. Koukourakis, Dina Tiniakos, Vassilis Kouloulias and Anna Zygogianni

Biomolecules 2024, 14(4), 448; https://doi.org/10.3390/biom14040448 - 6 Apr 2024

Viewed by 1455

Abstract

The IFN-type-I pathway is involved in radiotherapy (RT)-mediated immune responses. Large RT fractions have been suggested to potently induce this pathway. Neoadjuvant hypofractionated short-course (scRT) and conventional long-course (lcRT) RT applied for the treatment of locally advanced rectal adenocarcinoma patients provides a unique [...] Read more.

The IFN-type-I pathway is involved in radiotherapy (RT)-mediated immune responses. Large RT fractions have been suggested to potently induce this pathway. Neoadjuvant hypofractionated short-course (scRT) and conventional long-course (lcRT) RT applied for the treatment of locally advanced rectal adenocarcinoma patients provides a unique model to address the immuno-stimulatory properties of RT on a systemic level. We prospectively analyzed the IFNβ plasma levels and lymphocyte counts (LCs) of rectal adenocarcinoma patients before and after treatment with scRT (n = 22) and lcRT (n = 40). Flow cytometry was conducted to assess the effects on lymphocytic subpopulations in a subset of 20 patients. A statistically significant increase in the post-RT IFNβ plasma levels was noted in patients undergoing scRT (p = 0.004). Improved pathological tumor regression was associated with elevated post-RT IFNβ levels (p = 0.003). Although all patients experienced substantial lymphopenia after treatment, the post-RT LC of patients treated with scRT were significantly higher compared to lcRT (p = 0.001). Patients undergoing scRT displayed significantly lower percentages of regulatory CD4+/CD25+ T-cells after therapy (p = 0.02). scRT enables effective stimulation of the IFN-type-I pathway on a systemic level and confers decreased lymphocytic cytotoxicity and limited regulatory T-cell activation compared to lcRT, supporting its increasing role in immuno-RT trials. Full article

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2023

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18 pages, 1715 KiB

Open AccessReview

Recent Advances in Perioperative Immunotherapies in Lung Cancer

by Shota Fukuda, Kenichi Suda, Akira Hamada and Yasuhiro Tsutani

Biomolecules 2023, 13(9), 1377; https://doi.org/10.3390/biom13091377 - 12 Sep 2023

Cited by 4 | Viewed by 2879

Abstract

Several clinical trials have been revolutionizing the perioperative treatment of early-stage non-small cell lung cancer (NSCLC). Many of these clinical trials involve cancer immunotherapies with antibody drugs that block the inhibitory immune checkpoints programmed death 1 (PD-1) and its ligand PD-L1. While these [...] Read more.

Several clinical trials have been revolutionizing the perioperative treatment of early-stage non-small cell lung cancer (NSCLC). Many of these clinical trials involve cancer immunotherapies with antibody drugs that block the inhibitory immune checkpoints programmed death 1 (PD-1) and its ligand PD-L1. While these new treatments are expected to improve the treatment outcome of NSCLC patients after pulmonary resection, several major clinical questions remain, including the appropriate timing of immunotherapy (neoadjuvant, adjuvant, or both) and the identification of patients who should be treated with neoadjuvant and/or adjuvant immunotherapies, because some early-stage NSCLC patients are cured by surgical resection alone. In addition, immunotherapy may induce immune-related adverse events that will require permanent treatment in some patients. Based on this fact as well, it is desirable to select appropriate patients for neoadjuvant/adjuvant immunotherapies. So far, data from several important trials have been published, with findings demonstrating the efficacy of adjuvant atezolizumab (IMpower010 trial), neoadjuvant nivolumab plus platinum-doublet chemotherapy (CheckMate816 trial), and several perioperative (neoadjuvant plus adjuvant) immunotherapies (AEGEAN, KEYNOTE-671, NADIM II, and Neotorch trials). In addition to these key trials, numerous clinical trials have reported a wealth of data, although most of the above clinical questions have not been completely answered yet. Because there are so many ongoing clinical trials in this field, a comprehensive understanding of the results and/or contents of these trials is necessary to explore answers to the clinical questions above as well as to plan a new clinical trial. In this review, we comprehensively summarize the recent data obtained from clinical trials addressing such questions. Full article

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2022

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15 pages, 2528 KiB

Open AccessArticle

Shortened Hinge Design of Fab x sdAb-Fc Bispecific Antibodies Enhances Redirected T-Cell Killing of Tumor Cells

by Shuyu Huang, Aina Segués, Martin Waterfall, David Wright, Charlotte Vayssiere, Sander M. J. van Duijnhoven, Andrea van Elsas, Alice J. A. M. Sijts and Dietmar M. Zaiss

Biomolecules 2022, 12(10), 1331; https://doi.org/10.3390/biom12101331 - 21 Sep 2022

Viewed by 3049

Abstract

T cell engager (TCE) antibodies have emerged as promising cancer therapeutics that link cytotoxic T-cells to tumor cells by simultaneously binding to CD3E on T-cells and to a tumor-associated antigen (TAA) expressed by tumor cells. We previously reported a novel bispecific format, the [...] Read more.

T cell engager (TCE) antibodies have emerged as promising cancer therapeutics that link cytotoxic T-cells to tumor cells by simultaneously binding to CD3E on T-cells and to a tumor-associated antigen (TAA) expressed by tumor cells. We previously reported a novel bispecific format, the IgG-like Fab x sdAb-Fc (also known as half-IG_VH-h-CH2-CH3), combining a conventional antigen-binding fragment (Fab) with a single domain antibody (sdAb). Here, we evaluated this Fab x sdAb-Fc format as a T-cell redirecting bispecific antibody (TbsAbs) by targeting mEGFR on tumor cells and mCD3E on T cells. We focused our attention specifically on the hinge design of the sdAb arm of the bispecific antibody. Our data show that a TbsAb with a shorter hinge of 23 amino acids (TbsAb.short) showed a significantly better T cell redirected tumor cell elimination than the TbsAb with a longer, classical antibody hinge of 39 amino acids (TbsAb.long). Moreover, the TbsAb.short form mediated better T cell-tumor cell aggregation and increased CD69 and CD25 expression levels on T cells more than the TbsAb.long form. Taken together, our results indicate that already minor changes in the hinge design of TbsAbs can have significant impact on the anti-tumor activity of TbsAbs and may provide a new means to improve their potency. Full article

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25 pages, 1473 KiB

Open AccessReview

Advances in MUC1-Mediated Breast Cancer Immunotherapy

by Zhifeng Li, Dazhuang Yang, Ting Guo and Mei Lin

Biomolecules 2022, 12(7), 952; https://doi.org/10.3390/biom12070952 - 6 Jul 2022

Cited by 8 | Viewed by 4491

Abstract

Breast cancer (BRCA) is the leading cause of death from malignant tumors among women. Fortunately, however, immunotherapy has recently become a prospective BRCA treatment with encouraging achievements and mild safety profiles. Since the overexpression and aberrant glycosylation of MUC1 (human mucin) are closely [...] Read more.

Breast cancer (BRCA) is the leading cause of death from malignant tumors among women. Fortunately, however, immunotherapy has recently become a prospective BRCA treatment with encouraging achievements and mild safety profiles. Since the overexpression and aberrant glycosylation of MUC1 (human mucin) are closely associated with BRCA, it has become an ideal target for BRCA immunotherapies. In this review, the structure and function of MUC1 are briefly introduced, and the main research achievements in different kinds of MUC1-mediated BRCA immunotherapy are highlighted, from the laboratory to the clinic. Afterward, the future directions of MUC1-mediated BRCA immunotherapy are predicted, addressing, for example, urgent issues in regard to how efficient immunotherapeutic strategies can be generated. Full article

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2021

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3 pages, 148 KiB

Open AccessEditorial

Recent Advances in Cancer Immunotherapy

by Kenichi Suda

Biomolecules 2021, 11(2), 335; https://doi.org/10.3390/biom11020335 - 23 Feb 2021

Cited by 5 | Viewed by 2566

Abstract

The strategy to use the immune system to fight cancer is not a novel concept; in 1891, Coley reported the treatment of three cases of sarcoma by inoculation with erysipelas [...] Full article

2020

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19 pages, 518 KiB

Open AccessReview

The Possibilities of Immunotherapy for Children with Primary Immunodeficiencies Associated with Cancers

by Frederic Baleydier, Fanette Bernard and Marc Ansari

Biomolecules 2020, 10(8), 1112; https://doi.org/10.3390/biom10081112 - 28 Jul 2020

Cited by 6 | Viewed by 3110

Abstract

Many primary immunodeficiencies (PIDs) are recognised as being associated with malignancies, particularly lymphoid malignancies, which represent the highest proportion of cancers occurring in conjunction with this underlying condition. When patients present with genetic errors of immunity, clinicians must often reflect on whether to [...] Read more.

Many primary immunodeficiencies (PIDs) are recognised as being associated with malignancies, particularly lymphoid malignancies, which represent the highest proportion of cancers occurring in conjunction with this underlying condition. When patients present with genetic errors of immunity, clinicians must often reflect on whether to manage antitumoral treatment conventionally or to take a more personalised approach, considering possible existing comorbidities and the underlying status of immunodeficiency. Recent advances in antitumoral immunotherapies, such as monoclonal antibodies, antigen-specific adoptive cell therapies or compounds with targeted effects, potentially offer significant opportunities for optimising treatment for those patients, especially with lymphoid malignancies. In cases involving PIDs, variable oncogenic mechanisms exist, and opportunities for antitumoral immunotherapies can be considered accordingly. In cases involving a DNA repair defect or genetic instability, monoclonal antibodies can be proposed instead of chemotherapy to avoid severe toxicity. Malignancies secondary to uncontrolled virus-driven proliferation or the loss of antitumoral immunosurveillance may benefit from antivirus cell therapies or allogeneic stem cell transplantation in order to restore the immune antitumoral caretaker function. A subset of PIDs is caused by gene defects affecting targetable signalling pathways directly involved in the oncogenic process, such as the constitutive activation of phosphoinositol 3-kinase/protein kinase B (PI3K/AKT) in activated phosphoinositide 3-kinase delta syndrome (APDS), which can be settled with PI3K/AKT inhibitors. Therefore, immunotherapy provides clinicians with interesting antitumoral therapeutic weapons to treat malignancies when there is an underlying PID. Full article

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15 pages, 583 KiB

Open AccessEditor’s ChoiceReview

Significance of Immunosuppressive Cells as a Target for Immunotherapies in Melanoma and Non-Melanoma Skin Cancers

by Taku Fujimura and Setsuya Aiba

Biomolecules 2020, 10(8), 1087; https://doi.org/10.3390/biom10081087 - 22 Jul 2020

Cited by 39 | Viewed by 4134

Abstract

Tumor-associated macrophages (TAMs) have been detected in most skin cancers. TAMs produce various chemokines and angiogenic factors that promote tumor development, along with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tumor-associated neutrophils. TAMs generated from monocytes [...] Read more.

Tumor-associated macrophages (TAMs) have been detected in most skin cancers. TAMs produce various chemokines and angiogenic factors that promote tumor development, along with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tumor-associated neutrophils. TAMs generated from monocytes develop into functional, fully activated macrophages, and TAMs obtain various immunosuppressive functions to maintain the tumor microenvironment. Since TAMs express PD1 to maintain the immunosuppressive M2 phenotype by PD1/PD-L1 signaling from tumor cells, and the blockade of PD1/PD-L1 signaling by anti-PD1 antibodies (Abs) activate and re-polarize TAMs into immunoreactive M1 phenotypes, TAMs represent a potential target for anti-PD1 Abs. The main population of TAMs comprises CD163⁺ M2 macrophages, and CD163⁺ TAMs release soluble (s)CD163 and several proinflammatory chemokines (CXCL5, CXCL10, CCL19, etc.) as a result of TAM activation to induce an immunosuppressive tumor microenvironment together with other immunosuppressive cells. Since direct blockade of PD1/PD-L1 signaling between tumor cells and tumor-infiltrating T cells (both effector T cells and Tregs) is mandatory for inducing an anti-immune response by anti-PD1 Abs, anti-PD1 Abs need to reach the tumor microenvironment to induce anti-immune responses in the tumor-bearing host. Taken together, TAM-related factors could offer a biomarker for anti-PD1 Ab-based immunotherapy. Understanding the crosstalk between TAMs and immunosuppressive cells is important for optimizing PD1 Ab-based immunotherapy. Full article

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30 pages, 1678 KiB

Open AccessReview

Epigenetic Mechanisms of Resistance to Immune Checkpoint Inhibitors

by Alexandre Perrier, Audrey Didelot, Pierre Laurent-Puig, Hélène Blons and Simon Garinet

Biomolecules 2020, 10(7), 1061; https://doi.org/10.3390/biom10071061 - 16 Jul 2020

Cited by 64 | Viewed by 6684

Abstract

Immune checkpoint inhibitors (ICIs) have demonstrated to be highly efficient in treating solid tumors; however, many patients have limited benefits in terms of response and survival. This rapidly led to the investigation of combination therapies to enhance response rates. Moreover, predictive biomarkers were [...] Read more.

Immune checkpoint inhibitors (ICIs) have demonstrated to be highly efficient in treating solid tumors; however, many patients have limited benefits in terms of response and survival. This rapidly led to the investigation of combination therapies to enhance response rates. Moreover, predictive biomarkers were assessed to better select patients. Although PD-L1 expression remains the only validated marker in clinics, molecular profiling has brought valuable information, showing that the tumor mutation load and microsatellite instability (MSI) status were associated to higher response rates in nearly all cancer types. Moreover, in lung cancer, EGFR and MET mutations, oncogene fusions or STK11 inactivating mutations were associated with low response rates. Cancer progression towards invasive phenotypes that impede immune surveillance relies on complex regulatory networks and cell interactions within the tumor microenvironment. Epigenetic modifications, such as the alteration of histone patterns, chromatin structure, DNA methylation status at specific promoters and changes in microRNA levels, may alter the cell phenotype and reshape the tumor microenvironment, allowing cells to grow and escape from immune surveillance. The objective of this review is to make an update on the identified epigenetic changes that target immune surveillance and, ultimately, ICI responses, such as histone marks, DNA methylation and miR signatures. Translational studies or clinical trials, when available, and potential epigenetic biomarkers will be discussed as perspectives in the context of combination treatment strategies to enhance ICI responses in patients with solid tumors. Full article

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16 pages, 1855 KiB

Open AccessArticle

Vitamin D Prevents Pancreatic Cancer-Induced Apoptosis Signaling of Inflammatory Cells

by Stefania Moz, Nicole Contran, Monica Facco, Valentina Trimarco, Mario Plebani and Daniela Basso

Biomolecules 2020, 10(7), 1055; https://doi.org/10.3390/biom10071055 - 15 Jul 2020

Cited by 7 | Viewed by 2699

Abstract

Combined approaches based on immunotherapy and drugs supporting immune effector cell function might increase treatment options for pancreatic ductal adenocarcinoma (PDAC), vitamin D being a suitable drug candidate. In this study, we evaluated whether treatment with the vitamin D analogue, calcipotriol, counterbalances PDAC [...] Read more.

Combined approaches based on immunotherapy and drugs supporting immune effector cell function might increase treatment options for pancreatic ductal adenocarcinoma (PDAC), vitamin D being a suitable drug candidate. In this study, we evaluated whether treatment with the vitamin D analogue, calcipotriol, counterbalances PDAC induced and SMAD4-associated intracellular calcium [Ca²⁺]_i alterations, cytokines release, immune effector function, and the intracellular signaling of peripheral blood mononuclear cells (PBMCs). Calcipotriol counteracted the [Ca²⁺]_i depletion of PBMCs induced by SMAD4-expressing PDAC cells, which conditioned media augmented the number of calcium flows while reducing whole [Ca²⁺]_i. While calcipotriol inhibited spontaneous and PDAC-induced tumor necrosis factor alpha (TNF-α) release by PBMC and reduced intracellular transforming growth factor beta (TGF-β), it did not counteract the lymphocytes proliferation induced in allogenic co-culture by PDAC-conditioned PBMCs. Calcipotriol mainly antagonized PDAC-induced apoptosis and partially restored PDAC-inhibited NF-κB signaling pathway. In conclusion, alterations induced by PDAC cells in the [Ca²⁺]_i of immune cells can be partially reverted by calcipotriol treatment, which promotes inflammation and antagonizes PBMCs apoptosis. These effects, together with the dampening of intracellular TGF-β, might result in an overall anti-tumor effect, thus supporting the administration of vitamin D in PDAC patients. Full article

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17 pages, 728 KiB

Open AccessEditor’s ChoiceReview

The Resistance Mechanisms of Checkpoint Inhibitors in Solid Tumors

by Evangelos Koustas, Panagiotis Sarantis, Athanasios G. Papavassiliou and Michalis V. Karamouzis

Biomolecules 2020, 10(5), 666; https://doi.org/10.3390/biom10050666 - 25 Apr 2020

Cited by 33 | Viewed by 5603

Abstract

The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary [...] Read more.

The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary resistance to immunotherapy. Moreover, a significant number of patients who initially respond to treatment eventually acquire resistance to immunotherapy. Both resistance mechanisms are a result of a complex interaction among different molecules, pathways, and cellular processes. Several resistance mechanisms, such as tumor microenvironment modification, autophagy, genetic and epigenetic alterations, tumor mutational burden, neo-antigens, and modulation of gut microbiota have already been identified, while more continue to be uncovered. In this review, we discuss the latest milestones in the field of immunotherapy, resistance mechanisms against this type of therapy as well as putative therapeutic strategies to overcome resistance in solid tumors. Full article

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2019

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7 pages, 1758 KiB

Open AccessFeature PaperArticle

Comparison of PD-L1 Expression Status between Pure-Solid Versus Part-Solid Lung Adenocarcinomas

by Kenichi Suda, Masaki Shimoji, Shigeki Shimizu, Katsuaki Sato, Masato Chiba, Kenji Tomizawa, Toshiki Takemoto, Junichi Soh and Tetsuya Mitsudomi

Biomolecules 2019, 9(9), 456; https://doi.org/10.3390/biom9090456 - 7 Sep 2019

Cited by 11 | Viewed by 2927

Abstract

Although lung adenocarcinomas (LADs) with ground-glass opacity (GGO; part-solid tumors) have been shown to differ from those without GGO (pure-solid tumors) in clinicopathological features and prognoses, whether programmed death ligand-1 (PD-L1) protein expression differs between these two tumor types is unclear. This study [...] Read more.

Although lung adenocarcinomas (LADs) with ground-glass opacity (GGO; part-solid tumors) have been shown to differ from those without GGO (pure-solid tumors) in clinicopathological features and prognoses, whether programmed death ligand-1 (PD-L1) protein expression differs between these two tumor types is unclear. This study included 124 patients with clinical T1a–c LAD who received pulmonary resections during 2007–2009. The E1L3N antibody was used to stain for PD-L1 in primary LAD specimens. The specimens were considered PD-L1⁺ if ≥1% of tumor cells showed membrane staining, and were classified as having a high PD-L1⁺ tumor proportion score (TPS) if ≥50% of the tumor cells did so. Among the 124 patients, 45 had part-solid tumors and 79 had pure-solid tumors. These two groups did not significantly differ in terms of clinical factors. However, the rates for PD-L1 positivity (4% vs. 25%, p < 0.01) and high PD-L1⁺ TPS (2% vs. 16%, p = 0.02) were significantly higher in the pure-solid tumors. The multivariate analyses (logistic regression model) showed that the odds ratios for PD-L1 positivity and high PD-L1⁺ TPS in pure-solid LADs were 5.9 (95% CI; 1.2–29.7) and 8.0 (95% CI; 1.0–63.8), respectively. In conclusion, LADs with GGO were correlated with a lower incidence of PD-L1 expression than pure-solid tumors. Full article

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