Immunocheckpoint Inhibitors in Microsatellite-Stable or Proficient Mismatch Repair Metastatic Colorectal Cancer: Are We Entering a New Era?

Abstract

Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related deaths in Europe. About 5% of metastatic CRC (mCRC) are characterized by high microsatellite instability (MSI) due to a deficient DNA mismatch repair (dMMR), and this condition has been related to a high sensitivity to immunotherapy, in particular to the Immune Checkpoint Inhibitors (ICIs). In fact, in MSI-H or dMMR mCRC, treatment with ICIs induced remarkable response rates and prolonged survival. However, the majority of mCRC cases are mismatch-repair-proficient (pMMR) and microsatellite-stable (MSS), and unfortunately these conditions involve resistance to ICIs. This review aims to provide an overview of the strategies implemented to overcome ICI resistance and/or define subgroups of patients with MSS or dMMR mCRC who may benefit from immunotherapy.

Keywords: immunocheckpoint inhibitors; immunotherapy; metastatic colorectal cancer; microsatellite stability; proficient mismatch repair.

Figure 1

T-cell and tumor cell interaction mediated by activating or inhibitory immunological checkpoints and potential combination therapies to enhance efficacy. Agonistic or antagonist antibodies, by activating or inhibiting immunological checkpoints, lead to T-cell activation and expansion, and promote antitumor immune response. Combination strategies may enhance immunotherapy efficacy. OX40 or TNFRSF4: tumor necrosis factor (ligand) superfamily member 4; GITR: Glucocorticoid-Induced TNFR-Related; HVEM: Herpes Virus Entry Mediator; CTLA4: Cytotoxic T Lymphocyte Antigen-4; PD-1: programmed cell death-1; PD-L1: programmed cell death-1 ligand 1; TIM3: T cell immunoglobulin and mucin domain-containing protein 3; LAG-3: Lymphocyte Activation Gene-3 Protein; BTLA: B and T lymphocyte attenuator; VISTA: V-domain immunoglobulin suppressor of T cell activation; Gal9: Galectin-9; MHC: Major Histocompatibility Complex; VSIG-3: V-set and Ig domain-containing 3; Car-T: Chimeric Antigens Receptor T Cells; TIL: tumor infiltrating lymphocytes; Car-NK: Chimeric Antigens Receptor-Natural Killer Cells.