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Cancers
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Immunity and Gastrointestinal Cancer
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Immunity and Gastrointestinal Cancer

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

Deadline for manuscript submissions: closed (25 October 2023) | Viewed by 19316

Special Issue Editor

Dr. Joseph Chao

E-Mail Website
Guest Editor
Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA
Interests: stomach cancer; esophageal cancer; gastric cancer

Special Issue Information

Dear Colleagues,

Immunotherapy approaches have recently provided great benefits to patients affected across the spectrum of gastrointestinal cancers. However, the benefits are still not uniform for all patients, and predictive biomarkers remain limited. To date, only inhibitors of the PD-1 or CTLA-4 immune-checkpoint pathways have garnered regulatory approval in gastrointestinal cancers, highlighting the potential that further research into novel immunotherapy strategies and/or immune pathways may yield more positive outcomes for patients.

We are pleased to invite the submission of works covering clinical, translational, and/or basic science topics which contribute to an increased understanding of the intersection between immunity and gastrointestinal cancers.

This Special Issue aims to cover multiple facets of both preclinical and clinical research harnessing immune mechanisms to augment anti-tumor responses in all cancers of the gastrointestinal tract. This includes cancers affecting the esophagus, gastroesophageal junction, stomach, small bowel, liver, pancreas, colon, rectum, and anal canal.

In this Special Issue, original research articles and reviews are welcome. Research areas may include, but are not limited to, the following:

  1. Clinical trials utilizing immunotherapy approaches;
  2. Immune biomarker discovery (and/or validation);
  3. Impact of the fecal microbiome on immunotherapy;
  4. Basic science research on novel immune pathways or new understandings of established pathways.

We look forward to receiving your contributions.

Dr. Joseph Chao
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

  • gastrointestinal cancer
  • immunity
  • immunotherapy
  • tumor immune microenvironment
  • immune biomarkers
  • esophagogastric cancer
  • hepatobiliary cancer
  • pancreatic cancer
  • colorectal cancer
  • anal cancer

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Further information on MDPI's Special Issue policies can be found here.

Published Papers (7 papers)

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22 pages, 4562 KiB  
Article
How Toll-like Receptor 9 Plays a Key Role in the Development of Gastric Cancer and Is Linked to Epstein–Barr Virus Infection
by Marek Majewski, Paulina Mertowska, Sebastian Mertowski, Kamil Torres and Ewelina Grywalska
Cancers 2023, 15(20), 5104; https://doi.org/10.3390/cancers15205104 - 23 Oct 2023
Cited by 3 | Viewed by 1583
Abstract
The relationship between Toll-like receptor 9 (TLR-9) signaling and its involvement with Epstein–Barr virus (EBV) in gastric cancer (GC) is complex and currently under study. This research intended to understand TLR-9’s role in certain T and B lymphocytes and the serum levels of [...] Read more.
The relationship between Toll-like receptor 9 (TLR-9) signaling and its involvement with Epstein–Barr virus (EBV) in gastric cancer (GC) is complex and currently under study. This research intended to understand TLR-9’s role in certain T and B lymphocytes and the serum levels of TLR-9 in GC patients versus healthy subjects. The team explored links between these immune markers and various GC traits, such as histological grade, tumor progression stages, cancer types, and survival rates. Additionally, the research sought to find if EBV genetic material influences these immune reactions. Using flow cytometry, TLR-9 levels in different immune cells were analyzed. At the same time, the amount of TLR-9 in the serum was determined. The results showed GC patients had varied TLR-9 levels compared to healthy subjects, with specific cells showing noticeable changes. When grouped by GC attributes, key relationships emerged between TLR-9 amounts, the histological grade, progression stages, and cancer types. A notable finding was the connection between TLR-9 levels and EBV genetic presence, suggesting possible interactions between TLR-9 responses and EBV-related GC processes. Survival data also hinted at TLR-9’s potential as a predictor linked to clinical traits. Overall, this research emphasizes TLR-9’s complex role in GC’s immune responses, pinpointing its interactions with particular cells, clinical features, and EBV. The study unveils a complex web affecting GC and paves the way for new treatment avenues targeting TLR-9 pathways. Full article
(This article belongs to the Special Issue Immunity and Gastrointestinal Cancer)
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16 pages, 2891 KiB  
Article
Increased Response to Immune Checkpoint Inhibitors with Dietary Methionine Restriction in a Colorectal Cancer Model
by Lauren C. Morehead, Sarita Garg, Katherine F. Wallis, Camila C. Simoes, Eric R. Siegel, Alan J. Tackett and Isabelle R. Miousse
Cancers 2023, 15(18), 4467; https://doi.org/10.3390/cancers15184467 - 7 Sep 2023
Cited by 11 | Viewed by 2535
Abstract
Dietary methionine restriction (MR), defined as a reduction of methionine intake by around 80%, has been shown to reproducibly decrease tumor growth and synergize with cancer therapies. In this study, we combined DMR with immune checkpoint inhibitors (ICIs) in a model of colon [...] Read more.
Dietary methionine restriction (MR), defined as a reduction of methionine intake by around 80%, has been shown to reproducibly decrease tumor growth and synergize with cancer therapies. In this study, we combined DMR with immune checkpoint inhibitors (ICIs) in a model of colon adenocarcinoma. In vitro, we observed that MR increased the expression of MHC-I and PD-L1 in both mouse and human colorectal cancer cells. We also saw an increase in the gene expression of STING, a known inducer of type I interferon signaling. Inhibition of the cGAS–STING pathway, pharmacologically or with siRNA, blunted the increase in MHC-I and PD-L1 surface and gene expression following MR. This indicated that the cGAS–STING pathway, and interferon in general, played a role in the immune response to MR. We then combined dietary MR with ICIs targeting CTLA-4 and PD-1 in an MC38 colorectal cancer tumor model developed in immunocompetent C57BL/6 mice. The combination treatment was five times more effective at reducing the tumor size than ICIs alone in male mice. We noted sex differences in the response to dietary MR, with males showing a greater response than females. Finally, we observed an increase in membrane staining for the PD-L1 protein in MC38 tumors from animals who were fed an MR diet. MHC-I was highly expressed in all tumors and showed no expression difference when comparing tumors from control and MR-treated mice. These results indicated that MR increased PD-L1 expression both in vitro and in vivo and improved the response to ICIs in mice. Full article
(This article belongs to the Special Issue Immunity and Gastrointestinal Cancer)
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15 pages, 2346 KiB  
Article
Early Increase in Circulating PD-1+CD8+ T Cells Predicts Favorable Survival in Patients with Advanced Gastric Cancer Receiving Chemotherapy
by Kabsoo Shin, Joori Kim, Se Jun Park, Hyunho Kim, Myung Ah Lee, Okran Kim, Juyeon Park, Nahyeon Kang and In-Ho Kim
Cancers 2023, 15(15), 3955; https://doi.org/10.3390/cancers15153955 - 3 Aug 2023
Cited by 4 | Viewed by 1786
Abstract
The clinical significance of PD-1 expression in circulating CD8+ T cells in patients with gastric cancer (GC) receiving chemotherapy remains unelucidated. Therefore, we aimed to examine its prognostic significance in blood samples of 68 patients with advanced GC who received platinum-based chemotherapy. [...] Read more.
The clinical significance of PD-1 expression in circulating CD8+ T cells in patients with gastric cancer (GC) receiving chemotherapy remains unelucidated. Therefore, we aimed to examine its prognostic significance in blood samples of 68 patients with advanced GC who received platinum-based chemotherapy. The correlation between peripheral blood mononuclear cells, measured using fluorescence-activated cell sorting, was evaluated. Patients were divided into two groups according to the changes in PD-1+CD8+ T-cell frequencies between day 0 and 7. They were categorized as increased or decreased PD-1+CD8+ T-cell groups. The increased PD-1+CD8+ T-cell group showed longer progression-free survival (PFS) and overall survival (OS) than the decreased PD-1+CD8+ T-cell group (PFS: 8.7 months vs. 6.1 months, p = 0.007; OS: 20.7 months vs. 10.8 months, p = 0.003). The mean duration of response was significantly different between the groups (5.7 months vs. 2.5 months, p = 0.041). Multivariate analysis revealed that an increase in PD-1+CD8+ T-cell frequency was an independent prognostic factor. We concluded that the early increase in PD-1+CD8+ T-cell frequency is a potential predictor of favorable prognoses and durable responses in patients with advanced GC receiving chemotherapy. Full article
(This article belongs to the Special Issue Immunity and Gastrointestinal Cancer)
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14 pages, 3987 KiB  
Article
The Impact of Tumor Cell-Intrinsic Expression of Cyclic GMP-AMP Synthase (cGAS)-Stimulator of Interferon Genes (STING) on the Infiltration of CD8+ T Cells and Clinical Outcomes in Mismatch Repair Proficient/Microsatellite Stable Colorectal Cancer
by Shotaro Nakajima, Akinao Kaneta, Hirokazu Okayama, Katsuharu Saito, Tomohiro Kikuchi, Eisei Endo, Takuro Matsumoto, Satoshi Fukai, Mei Sakuma, Takahiro Sato, Kosaku Mimura, Motonobu Saito, Zenichiro Saze, Wataru Sakamoto, Hisashi Onozawa, Tomoyuki Momma and Koji Kono
Cancers 2023, 15(10), 2826; https://doi.org/10.3390/cancers15102826 - 18 May 2023
Cited by 5 | Viewed by 2471
Abstract
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in activating immune cells in the tumor microenvironment, thereby contributing to a more favorable response to immune checkpoint inhibitors (ICI) in colorectal cancer (CRC). However, the impact of the [...] Read more.
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in activating immune cells in the tumor microenvironment, thereby contributing to a more favorable response to immune checkpoint inhibitors (ICI) in colorectal cancer (CRC). However, the impact of the expression of cGAS-STING in tumor cells on the infiltration of CD8+ T cells and clinical outcomes in mismatch repair proficient/microsatellite stable (pMMR/MSS) CRC remains largely unknown. Our findings reveal that 56.8% of all pMMR CRC cases were cGAS-negative/STING-negative expressions (cGAS−/STING−) in tumor cells, whereas only 9.9% of all pMMR CRC showed cGAS-positive/STING-positive expression (cGAS+/STING+) in tumor cells. The frequency of cGAS+/STING+ cases was reduced in the advanced stages of pMMR/MSS CRC, and histone methylation might be involved in the down-regulation of STING expression in tumor cells. Since the expression level of cGAS-STING in tumor cells has been associated with the infiltration of CD8+ and/or CD4+ T cells and the frequency of recurrence in pMMR/MSS CRC, decreased expression of cGAS-STING in tumor cells might lead to poor immune cell infiltration and worse prognosis in most pMMR/MSS CRC patients. Our current findings provide a novel insight for the treatment of patients with pMMR/MSS CRC. Full article
(This article belongs to the Special Issue Immunity and Gastrointestinal Cancer)
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13 pages, 2186 KiB  
Article
NKG2D Fine-Tunes the Local Inflammatory Response in Colorectal Cancer
by Sophie Curio, Wanzun Lin, Christian Bromley, Jenny McGovern, Chiara Triulzi, Gustav Jonsson, Ghita Ghislat, Santiago Zelenay and Nadia Guerra
Cancers 2023, 15(6), 1792; https://doi.org/10.3390/cancers15061792 - 16 Mar 2023
Cited by 3 | Viewed by 2795
Abstract
Treating colorectal cancer (CRC) is a major challenge due to the heterogeneous immunological, clinical and pathological landscapes. Immunotherapy has so far only proven effective in a very limited subgroup of CRC patients. To better define the immune landscape, we examined the immune gene [...] Read more.
Treating colorectal cancer (CRC) is a major challenge due to the heterogeneous immunological, clinical and pathological landscapes. Immunotherapy has so far only proven effective in a very limited subgroup of CRC patients. To better define the immune landscape, we examined the immune gene expression profile in various subsets of CRC patients and used a mouse model of intestinal tumors to dissect immune functions. We found that the NK cell receptor, natural-killer group 2 member D (NKG2D, encoded by KLRK1) and NKG2D ligand gene expression is elevated in the most immunogenic subset of CRC patients. High level of KLRK1 positively correlated with the mRNA expression of IFNG and associated with a poor survival of CRC patients. We further show that NKG2D deficiency in the Apcmin/+ mouse model of intestinal tumorigenesis led to reduced intratumoral IFNγ production, reduced tumorigenesis and enhanced survival, suggesting that the high levels of IFNγ observed in the tumors of CRC patients may be a consequence of NKG2D engagement. The mechanisms governing the contribution of NKG2D to CRC progression highlighted in this study will fuel discussions about (i) the benefit of targeting NKG2D in CRC patients and (ii) the need to define the predictive value of NKG2D and NKG2D ligand expression across tumor types. Full article
(This article belongs to the Special Issue Immunity and Gastrointestinal Cancer)
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18 pages, 5827 KiB  
Article
An Immune Signature for Risk Stratification and Therapeutic Prediction in Helicobacter pylori-Infected Gastric Cancer
by Haigang Geng, Zhongyi Dong, Linmeng Zhang, Chen Yang, Tingting Li, Yuxuan Lin, Shouyu Ke, Xiang Xia, Zizhen Zhang, Gang Zhao and Chunchao Zhu
Cancers 2022, 14(13), 3276; https://doi.org/10.3390/cancers14133276 - 4 Jul 2022
Cited by 7 | Viewed by 3294
Abstract
Helicobacter pylori (HP) infection is the greatest risk factor for gastric cancer (GC). Increasing evidence has clarified that tumor immune microenvironment (TIME) is closely related to the prognosis and therapeutic efficacy of HP-positive (HP+) GC patients. In this study, we aimed to construct [...] Read more.
Helicobacter pylori (HP) infection is the greatest risk factor for gastric cancer (GC). Increasing evidence has clarified that tumor immune microenvironment (TIME) is closely related to the prognosis and therapeutic efficacy of HP-positive (HP+) GC patients. In this study, we aimed to construct a novel immune-related signature for predicting the prognosis and immunotherapy efficacy of HP+ GC patients. A total of 153 HP+ GC from three different cohorts were included in this study. An Immune-Related prognostic Signature for HP+ GC patients (IRSHG) was established using Univariate Cox regression, the LASSO algorithm, and Multivariate Cox regression. Univariate and Multivariate analyses proved IRSHG was an independent prognostic predictor for HP+ GC patients, and an IRSHG-integrated nomogram was established to quantitatively assessthe prognostic risk. The low-IRSHG group exhibited higher copy number load and distinct mutation profiles compared with the high-IRSHG group. In addition, the difference of hallmark pathways and immune cells infiltration between the two groups was investigated. Notably, tumor immune dysfunction and exclusion (TIDE) analysis indicated that the low-IRSHG group had a higher sensitivity to anti-PD-1 immunotherapy, which was validated by an external pabolizumab treatment cohort. Moreover, 98 chemotherapeutic drugs and corresponding potential biomarkers were identified for two groups, and several drugs with potential ability to reverse IRSHG score were identified using CMap analysis. Collectively, IRSHG may serve as a promising biomarker for survival outcome as well as immunotherapy efficacy. Furthermore, it can also help to prioritize potential therapeutics for HP+ GC patients, providing new insight for the personalized treatment of HP-infected GC. Full article
(This article belongs to the Special Issue Immunity and Gastrointestinal Cancer)
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Review

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14 pages, 891 KiB  
Review
The Roles of Immune Cells in Gastric Cancer: Anti-Cancer or Pro-Cancer?
by Asif Sukri, Alfizah Hanafiah and Nik Ritza Kosai
Cancers 2022, 14(16), 3922; https://doi.org/10.3390/cancers14163922 - 14 Aug 2022
Cited by 18 | Viewed by 3794
Abstract
Despite the fact that the incidence of gastric cancer has declined over the last decade, it is still the world’s leading cause of cancer-related death. The diagnosis of early gastric cancer is difficult, as symptoms of this cancer only manifest at a late [...] Read more.
Despite the fact that the incidence of gastric cancer has declined over the last decade, it is still the world’s leading cause of cancer-related death. The diagnosis of early gastric cancer is difficult, as symptoms of this cancer only manifest at a late stage of cancer progression. Thus, the prognosis of gastric cancer is poor, and the current treatment for improving patients’ outcomes involves the application of surgery and chemotherapy. Immunotherapy is one of the most recent therapies for gastric cancer, whereby the immune system of the host is programmed to combat cancer cells, and the therapy differs based upon the patient’s immune system. However, an understanding of the role of immune cells, namely the cell-mediated immune response and the humoral immune response, is pertinent for applications of immunotherapy. The roles of immune cells in the prognosis of gastric cancer have yielded conflicting results. This review discusses the roles of immune cells in gastric cancer pathogenesis, specifically, T cells, B cells, macrophages, natural killer cells, and dendritic cells, as well as the evidence presented thus far. Understanding how cancer cells interact with immune cells is of paramount importance in designing treatment options for gastric cancer immunotherapy. Full article
(This article belongs to the Special Issue Immunity and Gastrointestinal Cancer)
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