In Situ Detection of Individual Classic MHC-I Gene Products in Cancer

Gonzalez-Ericsson P.I.; Opalenik S.R.; Sanchez V.; Palubinsky A.M.; Hanna A.; Sun X.; Ocampo A.A.; Garcia G.; Maldonado L.; Morante Z.; Vidaurre T.; Valencia G.; Gomez H.L.; Sanders M.E.; Kennedy L.C.; Phillips E.J.; Balko J.M. · Cancer Immunology Research (2025) · DOI: 10.1158/2326-6066.cir-24-1003

Resumen

Tumor-specific HLA class I expression is required for cytotoxic T-cell elimination of cancer cells expressing tumor-associated antigens or neoantigens. Cancers downregulate antigen presentation to avoid adaptive immunity. The highly polymorphic nature of the genes encoding these proteins, coupled with quaternary-structure changes after formalin fixation, complicates detection by IHC. In this study, we determined recognition of 16 specific HLA-A, -B, and -C alleles by 15 antibodies commercially available for IHC use, identifying and validating pan and specific HLA-A, -B, and -C antibodies, providing a validated method that can be applied to investigate HLA-A, -B, and -C molecule–specific loss in cancer. We applied this approach to a series of breast cancers as a proof of utility, identifying differential HLA-A, -B, and -C loss, with a higher incidence of HLA-A and -B loss in hormone-driven breast cancers, HLA-B loss in HER2+ cancers, and an equal loss of all three molecules in triple-negative disease. Additionally, we found that at the protein level, HLA-A and -B loss were early events prevalent in premalignant lesions, whereas HLA-C loss was less common throughout tumor evolution. Effective response to immunotherapies such as checkpoint inhibitors and MHC-I–targeted cancer vaccines, which hinge on the carriage of specific allele groups, requires MHC-I expression on tumor cells. These findings have implications for the success of checkpoint inhibitors and vaccine strategies.