Gastrointestinal Cancer Immunotherapy: from Drug Resistance Mechanisms to Overcoming Strategies

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Background

Gastrointestinal (GI) cancers, including gastric cancer, colon cancer, liver cancer, esophageal cancer, and pancreatic cancer, seriously threaten the health of human beings worldwide with a high rate of morbidity and mortality. The clinical successes achieved with immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4 have opened a new cancer therapy era and brought new hope to cancer patients. However, the overall response rate (ORR) of ICI monotherapy in the non-selective population is only about 20%, in which some patients subsequently develop immunotherapy resistance. Moreover, the remaining 70-80% of patients displayed primary resistance to ICIs, and a few patients even experienced hyper progression disease (HPD). Although PD-L1 expression, mismatch repair deficient (MMRd), high tumor mutational burden (TMB-H) , high homologous recombination deficiency (HRD), and tumor infiltrated immune cells (TILs) are known as effective biomarkers for immunotherapy, growing studies have reported that ICIs could not improve the OS of all patients with PD-L1 expression higher than 50%, and the ORR of MSI-H patients was only about 60%, whereas some patients with low PD-L1 expression or MSS could still benefit from immunotherapy, indicating the complexity of ICI resistance. Therefore, it is of great importance and significance to explore the prediction biomarkers for primary or acquired immunotherapy resistance and elucidate their underlying molecular mechanisms and develop reversal strategies. Due to the multiple steps of the cancer immune cycle and complex immune microenvironment, any disorders of immune cell infiltration or T cell activation, such as lack of antigens and/or their presentation, lack of response to antigen presentation, and T cell priming, could contribute to ICI resistance. The combination with anti-angiogenesis therapy, radiotherapy, chemotherapy, and other ICIs has improved the efficacy of ICI therapy to some extent in the clinic. Although numerous studies related to ICI resistance were reported in GI cancers, due to the strong spatial/temporal heterogeneity and the complex immune microenvironment in different kinds of GI cancers and different individuals, many questions about ICI resistance and reversal strategies remain unsolved.

The aim of this Research Topic is to provide a forum to exhibit the latest research achievement related to the exploration of biomarkers for immunotherapy resistance including HPD and the underlying molecular mechanisms, as well as the development of reversal strategies in GI cancers. We hope this Research Topic will lead to a better understanding of precision cancer immunotherapy and provide useful clues for clinical application to benefit more GI cancer patients with immunotherapy.

We welcome high-quality Original Research articles, Review, Perspective, Opinion, and Case Reports focusing on resistance mechanisms and reversal strategies of immunotherapies in GI cancers, related to but not limited to the following subtopics:

1. Identification of immunotherapy resistance biomarkers or immune microenvironment characteristics based on multi-omics techniques, including bulk sequencing, single-cell sequencing, spatial transcriptome, liquid biopsy, gut microbiota, etc.

2. Novel technologies or clinical applications related to real-time dynamic monitoring of immunotherapy resistance.

3. Resistance mechanisms of ICI therapy involved in the disorders of any cancer immune cycle process (release and presentation of antigens, priming, and activation of T cells, trafficking and infiltration of T cells, recognition of cancer cells by T cells). The mechanisms can be investigated from multi-dimensions, such as specific gene mutation/amplification, abnormal signaling pathway, immunosuppressive cells and cytokines in the tumor microenvironment (TME), other immune checkpoints, epigenetic modification including ncRNA/DNA methylation /m5A methylation, protein post-translational modification including phosphorylation/acetylation/succinylation/glycosylation/ubiquitination, extracellular vesicles, and so on.

4. Novel immunotherapy resistance reversal strategies and mechanisms by normalizing TME, such as combined regimens with angiogenesis inhibitors/ chemotherapy/radiotherapy/other immune checkpoint inhibitors/adoptive cell therapies, development of novel targets and drugs, and so on.

Please note: Bioinformatic analysis or computational analysis using an online database needs further biological validation in vitro or in vivo. Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.

Keywords: Gastrointestinal cancer, immunology, Drug resistance, cancer, biomarkers

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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