The Mechanisms Leading to Distinct Responses to PD-1/PD-L1 Blockades in Colorectal Cancers With Different MSI Statuses

Abstract

Current clinical studies showed distinct therapeutic outcomes, in which CRC patients with mismatch repair-deficient (dMMR)/microsatellite instability high (MSI-H) seem to be relatively more “sensitive” in response to anti-programmed death-1 receptor (PD-1)/programmed death-1 receptor ligand 1 (PD-L1) therapy than those with mismatch repair-proficient (pMMR)/microsatellite instability-low (MSI-L). The mechanisms by which the same PD-1/PD-L1 blockades lead to two distinct therapeutic responses in CRC patients with different MSI statuses remain poorly understood and become a topic of great interest in both basic research and clinical practice. In this review of the potential mechanisms for the distinct response to PD-1/PD-L1 blockades between dMMR/MSI-H CRCs and pMMR/MSI-L CRCs, relevant references were electronically searched and collected from databases PubMed, MEDLINE, and Google scholar. Sixty-eight articles with full text and 10 articles by reference-cross search were included for final analysis after eligibility selection according to the guidelines of PRISMA. Analysis revealed that multiple factors e.g. tumor mutation burden, immune cell densities and types in the tumor microenvironment, expression levels of PD-1/PD-L1 and cytokines are potential determinants of such distinct response to PD-1/PD-L1 blockades in CRC patients with different MSI statuses which might help clinicians to select candidates for anti-PD-1/PD-L1 therapy and improve therapeutic response in patients with CRC.

Combined Gemcitabine and Immune-Checkpoint Inhibition Conquers Anti-PD-L1 Resistance in Low-Immunogenic Mismatch Repair-Deficient Tumors

“…Using a semi-autologous in vitro co-culture system, we provide evidence for the successful targeting of dMMR epithelial Mlh1 −/− murine tumor cells. However, the therapeutic outcome was highly individual among the two cell lines, A7450 T1 M1 and 328, nicely reflecting the heterogeneity among dMMR tumors patients, even in cases harboring the same MMR mutation [ 27 , 28 ]. The cell line Mlh1 −/− 328 is highly resistant and representative of a low-immunogenic subtype [ 21 , 22 ], which was confirmed further in this study.…”

Clinical Study of Sintilimab as Second-Line or Above Therapy in Patients With Advanced or Metastatic Gastric Cancer: A Retrospective Study

“…Some studies suggest that PD-L1 expression level, tumor mutational burden (TMB), Epstein–Barr virus (EBV) positive, and POLE gene mutation may be potential biomarkers to predict the efficacy of immunotherapy, but it has not been proved to be specific and effective enough, which is still controversial ( 21 ). At present, deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) is the only effective marker for anti-PD-1 treatment ( 22 , 23 ). However, in gastric cancer, MSI-H accounted for only 20%, and 80% of gastric cancer patients had microsatellite stability (MSS) ( 24 ).…”

Tumor response as defined by iRECIST in gastrointestinal malignancies treated with PD-1 and PD-L1 inhibitors and correlation with survival

“…Next, 48 patients with tumor diameter that maintained a < 20% increase from baseline had significantly reduced hazards of death (HR = 0.15, P = 0.01) after adjusting for age, combined surgery, KRAS status, cancer type, MMR, treatment course and cancer differentiation using multivariable analysis. According to previous research [ 23 – 25 ], deficient mismatch repair (dMMR) is a good predictor of the clinical benefit of PD-1/PD-L1 inhibitor therapy in many cancers, especially CRC. Based on MMR status, CRC patients can be divided into two subgroups based on the clinical benefit of immunotherapy: dMMR colorectal cancer (dominant population) and pMMR colorectal cancer (ineffective population).…”