Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer

Abstract

Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option.

Antitumor immunity in dMMR colorectal cancers requires interferon-induced CCL5 and CXCL10

“…Immune-associated genes are well known to be overexpressed in dMMR CRC but few studies have investigated the functional significance of these genes for the antitumor immune response. 1,3 Furthermore, most reports are based on whole tissue transcript analysis, making it difficult to determine the relative contribution of the CRC cells themselves to the expression of immune genes in the tissue. 23 In seeking to better understand the factors governing TIL recruitment into dMMR CRCs, we examined expression of various chemokines in data obtained from The Cancer Genome Atlas PanCancer Atlas data set.…”

“…Colorectal cancer (CRC) is a prevalent and often fatal disease initiated by either loss of the tumor suppressor APC or the DNA mismatch repair gene MLH1. 1,2 Whereas APC inactivation promotes large scale DNA damage leading to chromosomal instability (CIN), MLH1 inactivation promotes hypermutability in the form of genome-wide point mutations due to deficient mismatch repair (dMMR). Although accounting for only 15-20% of CRCs, dMMR CRCs are of particular interest due to their potent immune-stimulating capacity and overall favorable patient outcome.…”

Exploration of the role of tumor mutation burden in clinical significance, immunotherapy response predictor and immune cell infiltration in colon cancer

“…Based on these, TMB is becoming a hot biomarker for various cancers [29][30][31][32][33][34][35][36] . However, the role of TMB in colon cancer is still unde ned 14,34,36,37 . In this study, we rstly and comprehensively explored the role of tumor mutation burden in clinical signi cance, immunotherapy response predictor, and immune cell in ltration in colon cancer using TCGA database.…”

“…MSI in cancers is characterized by a tumor mutation burden (TMB), de ned as the number of DNA damages, including somatic single variant (SNV), insertions, deletions and frameshift mutations 12,13 . Previous studies demonstrated TMB was strong relative to immune checkpoint inhibitors (ICI) and immune cell in ltration in various cancers [14][15][16][17][18] , which are heavily associated with response to immunotherapy and tumor behavior [19][20][21] .…”

A Comprehensive Tumor Molecular Profile Analysis in Clinical Practice: A Single Center’s Experience

“…Moreover, alterations in DNA repair genes such as the MMR genes, POLE and HR genes have been shown to have a positive predictive effect and are correlated to increased TMB values (83)(84)(85)(86). In contrast, other gene alterations such as JAK1/2 and STK11/LKB1, KEAP1 and PTEN mutations are related to resistance to PD-1 Blockade (80,(87)(88)(89).…”