RESUMO
Background: Downregulation of MHC class I expression and/or defects in the antigen presentation pathways are commonly reported in human cancers. Numerous studies previously have explored extensively the molecular mechanisms that underlie HLA-class I and Beta2-Microglobulin (B2M) downregulation. However, the techniques presently available to detect expression of MHC class I proteins lack the robustness, specificity and sensitivity needed for systematic integration and analysis in clinical trials. Furthermore, the dynamics of HLA-class I and B2M expression have not been comprehensively studied as a potential biomarker for immunotherapy. Methods: Using novel, validated, immunohistochemistry (IHC)-based methods for quantifying B2M and HLA-A in tumor samples from diverse cancer types, we have determined loss of B2M and HLA-A proteins in 336 archived, primary specimens and 329 biopsies from metastatic patients collected during Roche-sponsored Phase 1 clinical trials investigating novel immunotherapy candidates as monotherapy or in combination with CPI. Results: Up to 56% of cases with B2M or HLA-A loss were noted in the investigated tumor types. The frequency of loss was dependent on indication and stage of disease and revealed heterogeneous expression patterns across patients. B2M and HLA-A loss was increased in metastatic lesions compared to primary tumors, indicating selection of MHC class I low clones in metastatic and refractory tumor cells. High on-treatment B2M expression correlated with successful clinical outcome (RECIST), while high baseline B2M did not. A treatment-induced increase of B2M expression was noted in most of the patients with low B2M levels at baseline. The triple biomarker combination of B2M, CD8 and PDL1 strongly improved response prediction to cancer immunotherapy. Conclusion: Our results indicate that B2M and HLA-A loss occurs frequently in tumors and is reversed in most instances following immunotherapy which supports the conclusion that MHC class I loss is not the dominant resistance mechanism to CPI treatment. This investigation reveals a highly dynamic expression of HLA-A and B2M in tumors affected by indication, metastatic status, immunophenotype and immunotherapy treatment. Baseline expression levels of B2M on tumors may be of utility as a constituent of a biomarker panel used for selecting patients for immunotherapy clinical trials.
