Editors' ChoiceCancer

The hidden agenda for immune escape in colorectal cancer

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Science Translational Medicine  27 Jun 2018:
Vol. 10, Issue 447, eaau1967
DOI: 10.1126/scitranslmed.aau1967


Multi-omic studies reveal immune evasion profiles in colorectal cancer.

Immunotherapy has advanced to the forefront of cancer treatment where it is providing new and effective options for patients. However, many patients do not respond to immunotherapy, and predictive biomarkers that can direct treatment have been elusive. Extensive efforts to detect biomarkers of immunotherapy response have focused on the characteristics of immune cells in the circulation and on cells and molecules in the tumor microenvironment. Much work also has centered on immunogenicity as measured by the burden of potential neoepitopes in the tumor. Another explanation for why some tumors respond to treatment while others do not may lie in genetic defects in antigen processing and presentation that prevent tumors from showing antigenic epitopes to T cells.

A recent report by Grasso et al. used a multi-omics approach to examine the landscape of immune editing and other potential mechanisms of tumor resistance to immune detection in colorectal cancer. The authors analyzed data from 1,211 primary tumors, including 179 from microsatellite instability-high (MSI-high) tumors, which are known to be more immunogenic. A variety of genes that encode the antigen processing machinery (APM) required for tumor presentation of antigenic epitopes to CD8+ T cells by human leukocyte antigen (HLA) class I molecules were found to be mutated more frequently than expected. B2M, the beta-chain of HLA class I, was substantially mutated in microsatellite stable (MSS) and MSI-high tumors, and HLA-A and HLA-B, alpha-chains of HLA molecules, were often mutated in MSI-high tumors. Frequent mutations were also identified in NLRC5 and RFX5, which regulate HLA class I transcription, and these mutations were associated with decreased HLA class I expression. Six of 75 MSI-high cases demonstrated biallelic disruption of TAP2 (required for peptide transport for loading onto HLA molecules), and 8 of 75 MSI-high cases demonstrated biallelic disruption of B2M.

Together, these findings demonstrate frequent defects in genes that mediate antigen processing and presentation by immunogenic colorectal cancers. These results have important implications as they suggest potential mechanisms of immune evasion that these tumors may employ to evade immune targeting. As the field of immunotherapy progresses, the study of the genetic mechanisms of immune evasion across a wide range of cancer types may be pivotal to the prediction of immunotherapy response and to elucidating obstacles to greater treatment success.

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