Why Don’t Immune Checkpoint Inhibitors Work in Colorectal Cancer?

Abstract

In recent years, immune checkpoint inhibitors have been shown to be effective in treating manifold types of cancer but less robust in colorectal cancer (CRC). While, the subgroup of CRC with microsatellite instability (MSI; also termed as mismatch repair deficient) showed a moderate response to Pembrolizumab in a single arm phase II clinical trial, microsatellite stable (MSS) cancers were unresponsive. Possible mechanisms that affect immune response in colorectal cancer will be reviewed in this article. We will also propose that histone deacetylase (HDAC) inhibition may reverse the immune editing commonly seen in advanced CRC and render them sensitive to immune checkpoint blockade.

Signal interaction between the tumour and inflammatory cells in patients with gastrointestinal cancer: Implications for treatment

“…improved prognosis associated with an increased inflammatory infiltrate in CRC as defined by the Immunoscore(106,107). The limited efficacy of anti-PD1 in CRC may be explained by the immune evasion stage of Immunoediting(108). One function of anti-PD1 is to increase the effector functions of T cells, but if the tumour cells develop mechanisms to evade the immune response then the T cells would be unable to recognise the tumour and exert these effector functions(108).…”

“…The limited efficacy of anti-PD1 in CRC may be explained by the immune evasion stage of Immunoediting(108). One function of anti-PD1 is to increase the effector functions of T cells, but if the tumour cells develop mechanisms to evade the immune response then the T cells would be unable to recognise the tumour and exert these effector functions(108). Alternatively, due to the heterogeneity of pathogenesis observed in CRC, other routes to tumourogenesis may out-compete the actions of anti-PD1.The gut harbours a unique combination of different cell types, which may account for why PD-1 blockade is unsuccessful in most CRC cases but successful in other cancer types (nonsmall cell lung cancer) (109).…”