Landscape of Immunotherapy Options for Colorectal Cancer: Current Knowledge and Future Perspectives beyond Immune Checkpoint Blockade

Abstract

Colorectal cancer is the third most prevalent malignancy in Western countries and a major cause of death despite recent improvements in screening programs and early detection methods. In the last decade, a growing effort has been put into better understanding how the immune system interacts with cancer cells. Even if treatments with immune checkpoint inhibitors (anti-PD1, anti-PD-L1, anti-CTLA4) were proven effective for several cancer types, the benefit for colorectal cancer patients is still limited. However, a subset of patients with deficient mismatch repair (dMMR)/microsatellite-instability-high (MSI-H) metastatic colorectal cancer has been observed to have a prolonged benefit to immune checkpoint inhibitors. As a result, pembrolizumab and nivolumab +/− ipilimumab recently obtained the Food and Drug Administration approval. This review aims to highlight the body of knowledge on immunotherapy in the colorectal cancer setting, discussing the potential mechanisms of resistance and future strategies to extend its use.

A Prognostic Model for Colon Adenocarcinoma Patients Based on Ten Amino Acid Metabolism Related Genes

“…There was only a small population of COAD patients who benefited from immunotherapy ( 39 – 42 ). Currently, TMB and MSI are the best predictors of the therapeutic effects of immune checkpoint inhibitors (ICIs) in COAD patients ( 43 , 44 ). We further analyzed the relationship between the risk score and MSI.…”

Targeting IL-34/MCSF-1R Axis in Colon Cancer

“…Antibody blockade of these immune checkpoints enhances the function of antitumor T cells, at least in part, by relieving inhibition of the T cell costimulatory receptor CD28 ( 48 ). Nevertheless, the durable responses induced by PD-1 or PD-L1 blockade alone can be limited in patients with CRC and the poor therapeutic effects have been linked to tumor-intrinsic or -extrinsic mechanisms for escaping immune surveillance ( 49 ).…”

Interference with pathways activated by topoisomerase inhibition alters the surface expression of PD‑L1 and MHC I in colon cancer cells

“…Cancer cells are known to respond to replication stress, chemotherapy, and radiation by activating DNA-damage response (DDR) and nuclear factor-κB (NF-κB) pathways (13)(14)(15)(16)(17)(18), both of which may serve as survival mechanisms for the cells damaged during therapy. Studies on CRC treatment to strategically combine chemotherapy, radiation, and immunotherapy are ongoing, with some encouraging preliminary results (19)(20)(21)(22)(23)(24)(25)(26). However, mechanistic studies on resistance mechanisms, and experiments to rationalize combination strategies are urgently needed (27).…”