T-cell immunoglobulin and ITIM domain, as a potential immune checkpoint target for immunotherapy of colorectal cancer.

The importance of the tumor microenvironment in cancer progression has been well studied for many years. Immune checkpoint inhibitors (ICIs) are regarded as potential strategies in enhancing the immune responses in patients with cancer, particularly colorectal cancer (CRC). Notably, CRCs are extraordinarily heterogeneous and mostly are microsatellite-stable (MSS) or cold tumors, which means that the immune response is not usually as strong as that of foreign cells. T-cell immunoglobulin and ITIM domain (TIGIT) is a new immune checkpoint receptor overexpressed inside the CRC tumor-immune microenvironments. Moreover, several studies have shown that TIGIT in combination with other ICIs and/or conventional treatments, can lead to a robust anti-tumor response in CRC. This review looks deep inside TIGIT expression patterns, their various functions, and possible immunotherapy strategies to increase survival rates and decrease immune-related adverse events.

Fathi M ，Pustokhina I ，Kuznetsov SV ，Khayrullin M ，Hojjat-Farsangi M ，Karpisheh V ，Jalili A ，Jadidi-Niaragh F ... -  《-》

Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: From bench to bedside.

Colorectal cancers (CRCs) with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) often have sustained responses to immune checkpoint inhibitors (ICIs) including selective monoclonal antibodies against Program Death 1 (PD-1), Programmed Death Ligand 1(PD-L1), and cytotoxic T lymphocyte associated antigen 4 (CTLA-4). However, a substantial fraction of dMMR CRCs do not respond or ultimately develop resistance to immunotherapy. The majority (~85%) of CRCs are MMR proficient (pMMR) or microsatellite stable (MSS) and lack response to ICIs. Understanding the biology and mechanisms underlying dMMR-associated immunogenicity is urgently needed for improving the therapeutic efficacy of immunotherapy on CRC. Compared to pMMR/MSS CRCs, dMMR/MSI CRCs typically have increased tumor mutational burden (TMB), lower response rate to 5-fluorouracil-based chemotherapy, distinctive immunological features such as high tumor-infiltrating lymphocytes (TILs), and better prognosis. Here, we review the current understanding of the clinical relevance of dMMR/MSI in CRCs, the molecular basis and rationales for targeting dMMR CRC with immunotherapy, and clinical approaches using ICIs as single agents or in combination with other therapies for MSI-H CRCs. Furthermore, we address the potential strategies to sensitize pMMR/MSS CRC to immunotherapy by converting an immunologically "cold" microenvironment into a "hot" one.

Lizardo DY ，Kuang C ，Hao S ，Yu J ，Huang Y ，Zhang L ... -  《-》

Application of PD-1 Blockade in Cancer Immunotherapy.

Wu X ，Gu Z ，Chen Y ，Chen B ，Chen W ，Weng L ，Liu X ... -  《Computational and Structural Biotechnology Journal》

Crosstalk Between the MSI Status and Tumor Microenvironment in Colorectal Cancer.

Colorectal cancer (CRC) patients, especially those with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) tumors, whose sensitivity to immune checkpoint inhibitors (ICIs) is significantly higher than that of patients with microsatellite-stable (MSS)/microsatellite instability-low (MSI-L) tumors, have derived clinical benefits from immunotherapy. Most studies have not systematically evaluated the immune characteristics and immune microenvironments of MSI-H and MSS/MSI-L CRCs. We analyzed the relationship between the MSI status and prognosis of ICI treatment in an immunotherapy cohort. We further used mutation data for the immunotherapy and The Cancer Genome Atlas (TCGA)-CRC [colon adenocarcinoma (COAD) + rectum adenocarcinoma (READ)] cohorts. For mRNA expression, mutation data analysis of the immune microenvironment and immunogenicity under different MSI statuses was performed. Compared with CRC patients with MSS/MSI-L tumors, those with MSI-H tumors significantly benefited from ICI treatment. MSI-H CRC had more immune cell infiltration, higher expression of immune-related genes, and higher immunogenicity than MSS/MSI-L CRC. The MANTIS score, which is used to predict the MSI status, was positively correlated with immune cells, immune-related genes, and immunogenicity. In addition, subtype analysis showed that COAD and READ might have different immune microenvironments. MSI-H CRC may have an inflammatory tumor microenvironment and increased sensitivity to ICIs. Unlike those of MSI-H READ, the immune characteristics of MSI-H COAD may be consistent with those of MSI-H CRC.

Lin A ，Zhang J ，Luo P 《Frontiers in Immunology》

Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer.

Pecci F ，Cantini L ，Bittoni A ，Lenci E ，Lupi A ，Crocetti S ，Giglio E ，Giampieri R ，Berardi R ... -  《-》