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Combined Treatment with Immunotherapy-Based Strategies for MSS Metastatic Colorectal Cancer.

ABSTRACT: In recent years, deepening knowledge of the complex interactions between the immune system and cancer cells has led to the advent of effective immunotherapies that have revolutionized the therapeutic paradigm of several cancer types. However, colorectal cancer (CRC) is one of the tumor types in which immunotherapy has proven less effective. While there is solid clinical evidence for the therapeutic role of immune checkpoint inhibitors in mismatch repair-deficient (dMMR) and in highly microsatellite instable (MSI-H) metastatic CRC (mCRC), blockade of CTLA-4 or PD-L1/PD-1 as monotherapy has not conferred any major clinical benefit to patients with MMR-proficient (pMMR) or microsatellite stable (MSS) mCRC, reflecting 95% of the CRC population. There thus remains a high unmet medical need for the development of novel immunotherapy approaches for the vast majority of patients with pMMR or MSS/MSI-low (MSI-L) mCRC. Defining the molecular mechanisms for immunogenicity in mCRC and mediating immune resistance in MSS mCRC is needed to develop predictive biomarkers and effective therapeutic combination strategies. Here we review available clinical data from combinatorial therapeutic approaches using immunotherapy-based strategies for MSS mCRC.

SUBMITTER: Baraibar I

PROVIDER: S-EPMC8699573 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Colorectal cancer (CRC) appears to be rather refractory to checkpoint blockers except the patient with deficient in mismatch repair (dMMR). Therefore, new advances in the treatment of most mismatch repair proficiency (pMMR) (also known as microsatellite stability, MSS) type of CRC patients are considered to be an important clinical issue associated with programmed death 1 (PD-1) inhibitors. In the present study, we evaluated the effects of gut microbiome of MSS-type CRC tumor-bearing mice treated with different antibiotics on PD-1 antibody immunotherapy response. Our results confirmed that the gut microbiome played a key role in the treatment of CT26 tumor-bearing mice with PD-1 antibody. After PD-1 antibody treatment, the injection of antibiotics counteracted the efficacy of PD-1 antibody in inhibiting tumor growth when compared with the Control group (mice were treated with sterile drinking water). Bacteroides_sp._CAG:927 and Bacteroidales_S24-7 were enriched in Control group. Bacteroides_sp._CAG:927, Prevotella_sp._CAG: 1031 and Bacteroides were enriched in Coli group [mice were treated with colistin (2 mg/ml)], Prevotella_sp._CAG:485 and Akkermansia_muciniphila were enriched in Vanc group [mice were treated with vancomycin alone (0.25 mg/ml)]. The metabolites were enriched in the glycerophospholipid metabolic pathway consistent with the metagenomic prediction pathway in Vanc group, Prevotella_sp._CAG:485 and Akkermansia may maintain the normal efficacy of PD-1 antibody by affecting the metabolism of glycerophospholipid. Changes in gut microbiome leaded to changes in glycerophospholipid metabolism level, which may affect the expression of immune-related cytokines IFN-γ and IL-2 in the tumor microenvironment, resulting in a different therapeutic effect of PD-1 antibody. Our findings show that changes in the gut microbiome affect the glycerophospholipid metabolic pathway, thereby regulating the therapeutic potential of PD-1 antibody in the immunotherapy of MSS-type CRC tumor-bearing mice.

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Combined Treatment with Immunotherapy-Based Strategies for MSS Metastatic Colorectal Cancer.

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