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Cancers
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Perspectives of Immunotherapy in Tumors of the Gastrointestinal Tract
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Perspectives of Immunotherapy in Tumors of the Gastrointestinal Tract

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (20 August 2022) | Viewed by 26242

Special Issue Editor

Dr. Gianluca Masi

E-Mail Website
Guest Editor
Department of Translational Research and New Technologies in Medicine, Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, 56121 Pisa, Italy
Interests: colorectal cancer; liver cancers; angiogenesis; immunotherapy; drugs development; multidisciplinary strategies

Special Issue Information

Dear Colleagues,

The use of immune-based therapies such as immune checkpoint inhibitors (ICIs) has become a standard therapy in various cancer types. The therapeutic application of monoclonal antibodies targeting inhibitory pathways such as programmed cell death-1(PD-1)/programmed cell death ligand 1 (PD-L1) and CTLA-4 has recently been shown to generate meaningful improvements in clinical outcomes, as well as in cancers of the gastrointestinal tract (mainly esophageal and gastric cancer, and colorectal cancer with microsatellite instability). Moreover, the combination of ICIs with antiangiogenic drugs is currently a new standard of care for hepatocellular carcinoma and such combinations are in active development in several cancers.

Despite these important results, much remains to be done to better select the patients who benefit most from immunotherapy, and to expand the number of responders.

The most relevant candidate predictors are microsatellite instability, PD-L1 expression, tumor mutational burden and DNA Polymerase Epsilon (POLE) or delta (POL-D) mutations. However, data on these biomarkers still require prospective validation. Furthermore, the complex interaction between gut microbiota and the human adaptive immune system will help to maximize response to these treatments.

We welcome submissions of research and review articles on the molecular mechanisms that contribute to the response to immune-based therapies in cancer of the gastrointestinal tract to bring together expert opinions and new advances from across the field in a Special Issue of Cancers. We welcome submissions that cover any relevant topic, including the role of immunotherapy, potential predictive factors, the role of gut microbiota, and new therapeutic opportunities including new drug combinations.

Prof. Gianluca Masi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • immunotherapy
  • angiogenesis
  • gastrointestinal cancer
  • liver cancer
  • hepato-biliary cancer
  • gut microbiota

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Published Papers (8 papers)

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Editorial

Jump to: Research, Review, Other

2 pages, 177 KiB  
Editorial
Editorial for Special Issue “Perspectives of Immunotherapy in Tumors of the Gastrointestinal Tract”
by Gianluca Masi
Cancers 2023, 15(4), 1223; https://doi.org/10.3390/cancers15041223 - 15 Feb 2023
Viewed by 1575
Abstract
After transforming the therapeutic perspective of many solid neoplasms, immunotherapy is finally making its way in the setting of gastro-intestinal (GI) primary cancers [...] Full article
(This article belongs to the Special Issue Perspectives of Immunotherapy in Tumors of the Gastrointestinal Tract)

Research

Jump to: Editorial, Review, Other

15 pages, 6097 KiB  
Article
Heat Shock Proteins 27, 70, and 110: Expression and Prognostic Significance in Colorectal Cancer
by Jan Hrudka, Karolína Jelínková, Hana Fišerová, Radoslav Matěj, Václav Mandys and Petr Waldauf
Cancers 2021, 13(17), 4407; https://doi.org/10.3390/cancers13174407 - 31 Aug 2021
Cited by 8 | Viewed by 2380
Abstract
Heat shock proteins (HSPs) are evolutionarily conserved chaperones occurring in virtually all living organisms playing a key role in the maintenance of cellular homeostasis. They are constitutively expressed to prevent and repair protein damage following various physiological and environmental stressors. HSPs are overexpressed [...] Read more.
Heat shock proteins (HSPs) are evolutionarily conserved chaperones occurring in virtually all living organisms playing a key role in the maintenance of cellular homeostasis. They are constitutively expressed to prevent and repair protein damage following various physiological and environmental stressors. HSPs are overexpressed in various types of cancers to provide cytoprotective function, and they have been described to influence prognosis and response to therapy. Moreover, they have been used as a tumor marker in blood serum biochemistry and they represent a potentially promising therapeutic target. To clarify prognostic significance of two canonical HSPs (27 and 70) and less known HSP110 (previously known as HSP105) in colorectal carcinoma (CRC), we retrospectively performed HSP immunohistochemistry on tissue microarrays from formalin-fixed paraffin-embedded tumor tissue from 297 patients with known follow-up. Survival analysis (univariate Kaplan–Meier analysis with the log-rank test and multivariate Cox regression) revealed significantly shorter overall survival (OS, mean 5.54 vs. 7.07, p = 0.033) and borderline insignificantly shorter cancer specific survival (CSS, mean 6.3 vs. 7.87 years, p = 0.066) in patients with HSP70+ tumors. In the case of HSP27+ tumors, there was an insignificantly shorter OS (mean 6.36 vs. 7.13 years, p = 0.2) and CSS (mean 7.17 vs. 7.95 years, p = 0.2). HSP110 showed no significant impact on survival. Using Pearson’s chi-squared test, there was a significant association of HSP27 and HSP70 expression with advanced cancer stage. HSP27+ tumors were more frequently mismatch-repair proficient and vice versa (p = 0.014), and they occurred more often in female patients and vice versa (p = 0.015). There was an enrichment of left sided tumors with HSP110+ compared to the right sided (p = 0.022). In multivariate Cox regression adjusted on the UICC stage, grade and right/left side; both HSPs 27 and 70 were not independent survival predictors (p = 0.616 & p = 0.586). In multivariate analysis, only advanced UICC stage (p = 0) and right sided localization (p = 0.04) were independent predictors of worse CSS. In conclusion, from all three HSPs examined in our study, only HSP70 expression worsened CRC prognosis, although stage-dependent. The contribution of this article may be seen as a large survival analysis of HSPs 27 and 70 and the largest analysis of HSP110 described in CRC. Full article
(This article belongs to the Special Issue Perspectives of Immunotherapy in Tumors of the Gastrointestinal Tract)
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Review

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17 pages, 333 KiB  
Review
Immune-Checkpoint Inhibitors (ICIs) in Metastatic Colorectal Cancer (mCRC) Patients beyond Microsatellite Instability
by Beatrice Borelli, Carlotta Antoniotti, Martina Carullo, Marco Maria Germani, Veronica Conca and Gianluca Masi
Cancers 2022, 14(20), 4974; https://doi.org/10.3390/cancers14204974 - 11 Oct 2022
Cited by 24 | Viewed by 3668
Abstract
Immune-checkpoint inhibitors (ICIs) showed impressive results in terms of activity and efficacy in metastatic colorectal cancer (mCRC) patients bearing tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). Despite that microsatellite status is the major predictive biomarker for the efficacy of [...] Read more.
Immune-checkpoint inhibitors (ICIs) showed impressive results in terms of activity and efficacy in metastatic colorectal cancer (mCRC) patients bearing tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). Despite that microsatellite status is the major predictive biomarker for the efficacy of ICIs, a proportion of dMMR/MSI-H mCRC tumors do not achieve benefit from immunotherapy due to the primary resistance. Deeper knowledge of biological mechanisms regulating dMMR/MSI-H CRC tumors and immune response may be useful to find new predictive biomarkers of ICIs benefit and tailor the use of immunotherapy even in dMMR/MSI-H mCRC patients. Moreover, several issues are still open, such as the secondary resection of metastases and the optimal duration of ICIs therapy in dMMR/MSI-H mCRC patients. Looking beyond microsatellite status, in a future perspective, several tools (i.e., Tumor Mutational Burden and PD-L1 expression) have been investigated to clarify their possible role as predictive biomarkers. Furthermore, a small subgroup of pMMR/MSS CRC tumors with a POLE mutation of the proofreading domain is characterized by hypermutated phenotype and might derive benefit from immune checkpoint inhibition. In the present work, we aim to review the most recent literature regarding treatment with ICIs in mCRC, focusing on dMMR/MSI-H and special subgroups of CRC patients. Hence, we summarize possible future targets and the most promising predictive biomarkers. Full article
(This article belongs to the Special Issue Perspectives of Immunotherapy in Tumors of the Gastrointestinal Tract)
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Graphical abstract

14 pages, 304 KiB  
Review
Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle
by Francesca Salani, Virginia Genovesi, Caterina Vivaldi, Valentina Massa, Silvia Cesario, Laura Bernardini, Miriam Caccese, Jessica Graziani, Dario Berra, Lorenzo Fornaro and Gianluca Masi
Cancers 2022, 14(19), 4896; https://doi.org/10.3390/cancers14194896 - 6 Oct 2022
Cited by 7 | Viewed by 3416
Abstract
Immune checkpoint inhibitors (ICIs) are a key component of different stages of hepatocellular carcinoma (HCC) treatment, particularly in the first line of treatment. A lesson on the primary resistance which hampers their efficacy and activity was learned from the failure of the trials [...] Read more.
Immune checkpoint inhibitors (ICIs) are a key component of different stages of hepatocellular carcinoma (HCC) treatment, particularly in the first line of treatment. A lesson on the primary resistance which hampers their efficacy and activity was learned from the failure of the trials which tested them as first-line mono-therapies. Despite the combination of anti-PD(L)1 agents with anti-VEGF, anti CTLA4, or TKIs demonstrating relevant improvements in efficacy, the “doublets strategy” still shows room for improvement, due to a limited overall survival benefit and a high rate of progressive disease as best response. In this review, we discuss the results from the currently tested doublet strategies (i.e., atezolizumab+bevacizumab, durvalumab+tremelimumab with a mention to the newly presented ICIs/TKIs combinations), which highlight the need for therapeutic improvement. Furthermore, we examine the rationale and provide an overview of the ongoing trials testing the treatment intensification strategy with triplet drugs: anti-PD1+anti-CTLA4+anti-VEGF/TKIs and anti-PD1+anti-VEGF+alternative immunity targets. Lastly, we report on the alternative strategy to integrate ICIs into the new paradigm of immune therapeutics constituted by CAR-T and anti-cancer vaccines. This review provides up-to-date knowledge of ongoing clinical trials of the aforementioned strategies and critical insight into their mechanistic premises. Full article
(This article belongs to the Special Issue Perspectives of Immunotherapy in Tumors of the Gastrointestinal Tract)
28 pages, 3046 KiB  
Review
Immunomodulation by Gut Microbiome on Gastrointestinal Cancers: Focusing on Colorectal Cancer
by Raghad Khalid AL-Ishaq, Lenka Koklesova, Peter Kubatka and Dietrich Büsselberg
Cancers 2022, 14(9), 2140; https://doi.org/10.3390/cancers14092140 - 25 Apr 2022
Cited by 13 | Viewed by 4208
Abstract
Gastrointestinal cancer (GI) is a global health disease with a huge burden on a patient’s physical and psychological aspects of life and on health care providers. It is associated with multiple disease related challenges which can alter the patient’s quality of life and [...] Read more.
Gastrointestinal cancer (GI) is a global health disease with a huge burden on a patient’s physical and psychological aspects of life and on health care providers. It is associated with multiple disease related challenges which can alter the patient’s quality of life and well-being. GI cancer development is influenced by multiple factors such as diet, infection, environment, and genetics. Although activating immune pathways and components during cancer is critical for the host’s survival, cancerous cells can target those pathways to escape and survive. As the gut microbiome influences the development and function of the immune system, research is conducted to investigate the gut microbiome–immune interactions, the underlying mechanisms, and how they reduce the risk of GI cancer. This review addresses and summarizes the current knowledge on the major immune cells and gut microbiome interactions. Additionally, it highlights the underlying mechanisms of immune dysregulation caused by gut microbiota on four major cancerous pathways, inflammation, cellular proliferation, apoptosis, and metastasis. Overall, gut-immune interactions might be a key to understanding GI cancer development, but further research is needed for more detailed clarification. Full article
(This article belongs to the Special Issue Perspectives of Immunotherapy in Tumors of the Gastrointestinal Tract)
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16 pages, 1500 KiB  
Review
Upper Gastrointestinal Cancer Surveillance in Lynch Syndrome
by Shria Kumar, Natalie Farha, Carol A. Burke and Bryson W. Katona
Cancers 2022, 14(4), 1000; https://doi.org/10.3390/cancers14041000 - 16 Feb 2022
Cited by 10 | Viewed by 4166
Abstract
Lynch syndrome is a common hereditary cancer predisposition syndrome associated with increased digestive cancer risk including colorectal, gastric, and duodenal cancers. While colorectal cancer surveillance is widely accepted to be an important part of a comprehensive Lynch syndrome risk management plan, the use [...] Read more.
Lynch syndrome is a common hereditary cancer predisposition syndrome associated with increased digestive cancer risk including colorectal, gastric, and duodenal cancers. While colorectal cancer surveillance is widely accepted to be an important part of a comprehensive Lynch syndrome risk management plan, the use of upper gastrointestinal cancer surveillance in Lynch syndrome remains more controversial. Currently, upper gastrointestinal cancer surveillance guidelines for Lynch syndrome vary widely, and there is no consensus on who should undergo upper gastrointestinal cancer surveillance, how surveillance should be performed, the age at which to initiate surveillance, or how often individuals with Lynch syndrome should undergo upper gastrointestinal cancer surveillance. Fortunately, research groups around the world have been focusing on upper gastrointestinal cancer surveillance in Lynch syndrome, and recent evidence in this field has demonstrated that upper gastrointestinal cancer surveillance can be performed with identification of precancerous lesions as well as early-stage upper gastrointestinal cancers. In this manuscript, we review the upper gastrointestinal cancer risks in Lynch syndrome, differing guideline recommendations for surveillance, outcomes of upper gastrointestinal cancer surveillance, and controversies in the field, and we provide a framework based on our collective experience with which to incorporate upper gastrointestinal cancer surveillance into a risk management program for individuals with Lynch syndrome. Full article
(This article belongs to the Special Issue Perspectives of Immunotherapy in Tumors of the Gastrointestinal Tract)
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Other

9 pages, 255 KiB  
Commentary
The Evolving Landscape of Immunotherapy in Locally Advanced Rectal Cancer Patients
by Marco Maria Germani, Martina Carullo, Alessandra Boccaccino, Veronica Conca and Gianluca Masi
Cancers 2022, 14(18), 4453; https://doi.org/10.3390/cancers14184453 - 14 Sep 2022
Cited by 5 | Viewed by 2354
Abstract
Standard treatments of localized rectal cancer are surgery or the multimodal approach with neoadjuvant treatments (chemo-radiotherapy, short-course radiotherapy, induction, or consolidation chemotherapy) followed by surgery. In metastatic colorectal cancer (mCRC), immune checkpoint inhibitors (ICIs) are now the first choice in patients with a [...] Read more.
Standard treatments of localized rectal cancer are surgery or the multimodal approach with neoadjuvant treatments (chemo-radiotherapy, short-course radiotherapy, induction, or consolidation chemotherapy) followed by surgery. In metastatic colorectal cancer (mCRC), immune checkpoint inhibitors (ICIs) are now the first choice in patients with a deficient mismatch repair system/microsatellite instability (dMMR/MSI-H) and are being explored in combination with chemotherapy to rewire the immune system against malignant cells in subjects with proficient mismatch repair system/microsatellite low (pMMR/MSI-L) cancers, with promising signals of efficacy. Recently, some efforts have been made to translate ICIs in earlier stages of CRC, including localized rectal cancer, with breakthrough efficacy and an organ preservation rate of mono-immunotherapy in dMMR/MSI-H patients and promising anti-tumor activity of immunotherapy plus neoadjuvant (chemo)radiotherapy in pMMR/MSI-L subjects. Here, we present the rationale, results, and limitations of the most remarkable trials assessing ICIs in dMMR/MSI-H and pMMR/MSI-L localized rectal cancer patients, at the same time highlighting the most promising research perspectives that have followed these studies. Full article
(This article belongs to the Special Issue Perspectives of Immunotherapy in Tumors of the Gastrointestinal Tract)
8 pages, 235 KiB  
Commentary
Immune Checkpoint Inhibitors in Mismatch Repair Proficient/Microsatellite Stable Metastatic Colorectal Cancer Patients: Insights from the AtezoTRIBE and MAYA Trials
by Marco Maria Germani and Roberto Moretto
Cancers 2022, 14(1), 52; https://doi.org/10.3390/cancers14010052 - 23 Dec 2021
Cited by 11 | Viewed by 3278
Abstract
In metastatic colorectal cancer (mCRC), remarkable advances have been achieved with immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4, only in a small subset of tumours (4–5%), harbouring a deficient mismatch repair system (dMMR)/microsatellite instability–high (MSI-H) or mutations in the catalytic subunit of [...] Read more.
In metastatic colorectal cancer (mCRC), remarkable advances have been achieved with immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4, only in a small subset of tumours (4–5%), harbouring a deficient mismatch repair system (dMMR)/microsatellite instability–high (MSI-H) or mutations in the catalytic subunit of polymerase epsilon (POLE). Within this framework, several combination strategies have been investigated to sensitize proficient mismatch repair (pMMR)/microsatellite stable (MSS) mCRC to ICIs, with disappointing results so far. However, at the last ESMO meeting, two phase II trials AtezoTRIBE and MAYA provided promising results in this field. In the comparative AtezoTRIBE trial, the addition of atezolizumab to FOLFOXIRI (5-fluoruracil, oxaliplatin and irinotecan) and bevacizumab led to a significant advantage in terms of progression free survival (PFS) in a population of untreated mCRC patients, not selected according to MMR/MSI status. In the single-arm MAYA trial, immune priming with temozolomide in pMMR/MSS chemo-resistant mCRC patients with silencing of O6-methylguanine-DNA methyltransferase (MGMT) allowed reporting signals of sensitivity to the subsequent therapy with nivolumab and a low dose of ipilimumab in some patients. Here, we discuss the rationale, results, criticisms and research perspectives opened by these two studies. Full article
(This article belongs to the Special Issue Perspectives of Immunotherapy in Tumors of the Gastrointestinal Tract)
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