Immune checkpoint blockade therapy (ICBT) has resulted in extended overall survival for some patients with certain types of cancer, most prominently including colorectal cancer (CRC) associated with microsatellite instability (MSI). However, most patients with CRC whose phenotypes have microsatellite stability (MSS) are unresponsive to ICBT. In efforts to understand the responsiveness of CRC tumors to ICBT, genotypic and phenotypic signatures of CRC tumors are now being investigated. The MSI and MSS classification has been clinically validated as helpful in predicting response vs nonresponse to ICBT in patients with CRC. Other potential predictive markers include mutational and neoantigen loads, T-cell receptor diversity, and the immune score system, all of which have mechanistic connections to ICBT response. These novel predictive signatures could provide unprecedented insights into patients with CRC associated with MSS. Clinical trials or prospective cohort studies using standardized methodologies for biomarker quantification should be illuminating. Further validation of these novel predictive signatures will be essential to tailoring treatment of patients whose CRC is most likely to respond to ICBT.
Bibliographical noteFunding Information:
S.S. is supported by research grants funded by the NIH/NCI grant R03CA219129 and Mezin-Koats Colon Cancer Research Fund ; A.M., by the Life Sciences Summer Undergraduate Research Program ; and X.Z., by a research fellowship from the Department of Surgery, University of Minnesota . Because of space restrictions, the authors cannot cite the many significant contributions made by numerous researchers and laboratories in this potentially important and rapidly progressing field. The authors are grateful to Dr. Mary Knatterud for assisting in manuscript preparation.