Current status of immunotherapy against gastrointestinal cancers and its biomarkers: Perspective for precision immunotherapy

Abstract

Immunotherapy has shown encouraging results for some types of tumor. Although enormous efforts have been made toward the development of specific immunotherapeutic strategies against gastrointestinal cancers, such as adoptive T‐cell transfer, peptide vaccines, or dendritic cell vaccines, the efficacy of immunotherapies prior to the introduction of immune checkpoint inhibitors was not substantial. This article reviews immunotherapy for gastrointestinal malignancies, including cell therapy, peptide vaccine, and immune checkpoint inhibitors, and attempts to resolve the immunosuppressive conditions surrounding the tumor microenvironment, and to construct novel combination immunotherapies beyond immune checkpoint inhibitors.

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

“…Immune checkpoint inhibitors (ICIs), including pembrolizumab (Keytruda) and nivolumab (Opdivo), antibodies against programmed death-1 (PD-1), recently gained Food and Drug Administration (FDA) approval for use in GI cancers (Table 1) (6)(7)(8)(9)(10)(11). While their approval has been a significant step forward in advancing clinical care, currently, few patients benefit (12). Patients benefiting the most tend to have tumors harboring deficient DNA mismatch repair (dMMR) and high microsatellite instability (MSI-H) (8,13).…”

“…MSI-H tumors account for 6-22% of gastric, 1% of pancreatic, 3% of liver, and 14-16% of colorectal cancers (22)(23)(24)(25)(26)(27). Antibodies against PD-1/programmed death-ligand 1 (PD-L1) or cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) are the most clinically advanced immunotherapy in cancer (12). The PD-1/PD-L1 axis promotes adaptive immune resistance by suppressing effector T cells and promoting the differentiation of regulatory T cells (Tregs).…”

“…The PD-1/PD-L1 axis promotes adaptive immune resistance by suppressing effector T cells and promoting the differentiation of regulatory T cells (Tregs). CTLA-4 also is a negative regulator of T cells; its engagement of B7-1 or B7-2 on antigen-presenting cells inhibits T cell activation (12). Preclinical and clinical efforts are pushing forward with combination ICI therapy as well as ushering in different approaches to harness the immune system to extend immunotherapy efficacy to more patients, including vaccines and viral therapy, adoptive cell transfer, and cytokine treatment (12,28).…”

“…CTLA-4 also is a negative regulator of T cells; its engagement of B7-1 or B7-2 on antigen-presenting cells inhibits T cell activation (12). Preclinical and clinical efforts are pushing forward with combination ICI therapy as well as ushering in different approaches to harness the immune system to extend immunotherapy efficacy to more patients, including vaccines and viral therapy, adoptive cell transfer, and cytokine treatment (12,28). Challenges with improving efficacy include overcoming immunosuppression activity by the tumor microenvironment, unmasking pre-existing immune cell activity, and the ability to stimulate de novo immunogenicity (29).…”

Immunologic Biomarkers and Biomarkers for Immunotherapies in Gastrointestinal Cancer

“…In the following, we will only give a rough overview. Concerning the details we refer to recently published excellent reviews that summarize the clinical aspects of immuno-oncology in GI cancers [7-9, 53]. …”