Inter-patient and intra-tumor heterogeneity in the sensitivity to tumor-targeted immunity in colorectal cancer

Efficacy of immune checkpoint inhibitors such as PD-1 antibody for colorectal cancer remains to be proved except in microsatellite- instability-high (MSI-H) cases. While the objective response rate of MSI-H cases was 40%, that of microsatellite-stable (MSS) cases was 0%, showing that response rate to immune checkpoint inhibitors varies even among the microsatellite status. Some possible mechanisms that confer each patient variation in the response to immunotherapy should be considered. We focused on the combination of inter-patient heterogeneity and intra-tumor heterogeneity as a determining factor of immune reaction. An example of intra-tumor heterogeneity is the low expression of tumor antigen by CD271+ cells in melanoma. It is not surprising that similar mechanism exists in CRC. Other related intra-tumor heterogeneity includes EMT and autophagy, both molecular mechanisms that are thought to promote immune-evading phenotype. Besides the microsatellite status, inter- patient heterogeneity in response to tumor immunity includes hypermutator phenotype, which is driven by POLE mutation, intrinsic cytokine production, and microbiota in the gut.