Immunotherapy with immune checkpoint inhibitors in colorectal cancer: what is the future beyond deficient mismatch-repair tumours?

Abstract

Following initial success in melanoma and lung tumours, immune checkpoint inhibitors (ICIs) are now well recognized as a major immunotherapy treatment modality for multiple types of solid cancers. In colorectal cancer (CRC), the small subset that is mismatch-repair-deficient and microsatellite-instability-high (dMMR/MSI-H) derive benefit from immunotherapy; however, the vast majority of patients with proficient MMR (pMMR) or with microsatellite stable (MSS) CRC do not. Immunoscore and the consensus molecular subtype classifications are promising biomarkers in predicting therapeutic efficacy in selected CRC. In pMRR/MSS CRC, biomarkers are also needed to understand the molecular mechanisms governing immune reactivity and to predict their relationship to treatment. The continuous development of such biomarkers would offer new perspectives and more personalized treatments by targeting oncological options, including ICIs, which modify the tumour-immune microenvironment. In this review, we focus on CRC and discuss the current status of ICIs, the role of biomarkers to predict response to immunotherapy, and the approaches being explored to render pMMR/MSS CRC more immunogenic through the use of combined therapies.

Keywords: colorectal cancer; immune checkpoint inhibitors; immune response; immunoscore; immunotherapy.

Figure 1.

Schematic representation of colorectal-cancer-immune subgroups, linked biomarkers, and potential treatment strategies. ‘Immunocompetent’ tumour (green circle) is characterized by a coordinated immune response with high T-cells (CD3, CD8, and Th1), macrophage infiltration, and upregulation of immune checkpoint molecules (CTLA-4, PD-1, and PD-L1). ‘Immune evasion’ group (blue circle) is characterized by poor immune cell infiltration. ‘Immunosuppressed’ group (red circle) is characterized by high immune cell infiltration as well as a high infiltration of suppressor cells with suppressive cytokine release. The ‘immune evasion’ and the ‘immunosuppressed’ groups could be treated with radiotherapy, chemotherapy, targeted therapy, cytokine modulation, or other approaches such as COX inhibition or A2AR inhibition, to render the tumours more immunogenic so that they benefit from ICIs. Possible biomarkers of response to ICIs are marked from 1 to 6. (1) PD-1/PD-L1 expression. (2) Tumour-mutation burden. (3) Mutation-associated neoantigens presentation on HLA class I. (4) High cytotoxic immune cells infiltration (immunoscore). (5) Gene-expression signature (including CMS classification). (6) Gut microbiome. A2AR, adenosine A2A receptor; COX, cyclooxygenase-2; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; HLA, human leucocyte antigens; IFN-γ, interferon-gamma; IL-17, interleukin 17; MDSC, myeloid-derived suppressor-derived cells; PD-1, programmed death protein 1; PD-L1, programmed death-ligand 1; TCR, T-cell receptor; TGF-β, transforming growth factor-beta; Th17, T helper 17; CMS, consensus molecular subtype.