Dynamic Tumor-Specific MHC-II Immuno-PET Predicts Checkpoint Inhibitor Immunotherapy Efficacy in Melanoma

Abstract

Despite the advance of immunotherapy, only a small subset of patients gains long-term survival benefit. It warrants a compelling rationale to develop immuno-PET imaging that could predict tumor response to the immunotherapy. An increasing number of studies have shown that tumor-specific major histocompatibility complex II (tsMHC-II) associates with improved responses to targeted immunotherapy. The aim of this study was to investigate the potential of tsMHC-II protein expression and its dynamic change upon treatment with interferon γ (IFNγ) as a new target for immuno-PET to predict response to immunotherapy. Methods: MHC-II antibody was radiolabeled with DOTA-chelated ⁶⁴Cu to derive an MHC-II immuno-PET tracer. Two melanoma models models (B16SIY, B16F10), which are respondent and non-respondent to PD1/PD-L1 checkpoint inhibitor, respectively, were used. Both tumor models were treated with anti-PD1 and IFNγ, which enabled observation of dynamic change of tsMHC-II. Small-animal PET imaging, biodistribution and histological studies were performed to validate the correlation of tsMHC-II with the tumor response to the immunotherapy. Results: FACS analysis of the two tumors supported the consensual recognition of tsMHC-II correlated to the tumor response to the immunotherapy. The in vivo PET imaging revealed higher basal levels of tsMHC-II in the responder, B16SIY, than in the non-responder, B16F10. When treated with anti-PD1 antibody in animals, B16SIY tumors displayed a sensitive increase of tsMHC-II compared to B16F10 tumors. In IFNγ stimulation groups, the greater magnitude of tsMHC-II was further amplified when the IFNγ signaling is activated in the B16SIY tumors, which positively upregulates tsMHC-II in the tumor immunity. Subsequent histopathological analysis supported the correlative characteristics of tsMHC-II with tumor immunity and response to cancer immunotherapy. Conclusion: Collectively, the predictive value of tsMHC-II immuno-PET was validated for stratifying tumor immunotherapy responders vs. non-responders. Monitoring sensitivity of tsMHC-II to IFNγ stimulation may provide an effective strategy to predict the tumor response to immunotherapy.