Immunotherapy in colorectal cancer: current achievements and future perspective

Abstract

Following dramatic success in many types of advanced solid tumors, interest in immunotherapy for the treatment of colorectal cancer (CRC) is increasingly growing. Given the compelling long-term durable remission, two programmed cell death 1 (PD-1)-blocking antibodies, pembrolizumab and nivolumab (with or without Ipilimumab), have been approved for the treatment of patients with metastatic colorectal cancer (mCRC) that is mismatch-repair-deficient and microsatellite instability-high (dMMR-MSI-H). Practice-changing results of several randomized controlled trials to move immunotherapy into the first-line treatment for MSI-H metastasis cancer and earlier stage were reported successively in the past 2 years. Besides, new intriguing advances to expand the efficacy of immunotherapy to mCRC that is mismatch-repair-proficient and low microsatellite instability (pMMR-MSI-L) demonstrated the potential benefits for the vast majority of mCRC cases. Great attention is also paid to the advances in cancer vaccines and adoptive cell therapy (ACT). In this review, we summarize the above progresses, and also highlight the current predictive biomarkers of responsiveness in immunotherapy with broad clinical utility.

Keywords: adoptive cell therapy; biomarkers; cancer vaccines; colorectal cancer; immune checkpoint inhibitors; immunotherapy.

Figure 1

The process of an antitumor response. Tumor cells generate and release neoantigens which could be phagocytosed by dendritic cells (DC). Next, DC mediated presentation of tumor-specific antigens to CD8+ T cells and CD4+ helper T type1 cells which could enhance the effects of CD8+ T cells on killing tumor and promote the generation of tumor-specific activated T cells and memory T cells. Finally, tumor cells are destructed by effector T cells, which could be inhibited by regulatory T cells (Tregs), M2-polarized tumor-associated macrophage (M2 TAMs), myeloid-derived suppressor cells (MDSCs) and immature DC.

Figure 2

The rationale of combination strategies to overcome primary ICI resistance in CRC. MEKi: MEK inhibitor; Tregs: regulatory T cells; TAMs: tumor-associated macrophage; MDSCs: myeloid- derived suppressor cells; APCs: antigen presenting cells; DC: dendritic cells; IAA: immune-associated antigen; TAA: tumor-associated antigen.

Figure 3

Potential biomarkers of CRC immunotherapy. TMB: tumor mutational burden; MSI-H: microsatellite instability-high; dMMR: mismatch-repair-deficient; TILs: tumor infiltrating lymphocytes; B2M: beta-2-microglobulin; B. pseudolongum: Bifidobacterium pseudolongum; L. johnsonii: Lactobacillus johnsonii; Olsenella sp.:Olsenella species; A. muciniphila: Akkermansia muciniphila.