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

Abstract

Despite the advance of immunotherapy, only a small subset of patients gains long-term survival benefit. This fact represents a compelling rationale to develop immuno-PET imaging that can predict tumor response to immunotherapy. An increasing number of studies have shown that tumor-specific major histocompatibility complex II (tsMHC-II) is associated 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 on treatment with interferon γ (IFNγ) as a new target for immuno-PET to predict response to immunotherapy. Methods: Major histocompatibility complex II (MHC-II) antibody was radiolabeled with DOTA-chelated 64Cu to derive an MHC-II immuno-PET tracer. Two melanoma models (B16SIY, B16F10) that are respondent and nonrespondent, respectively, to PD1/PD-L1 checkpoint inhibitor were used. Both tumor models were treated with anti-PD1 and IFNγ, enabling observation of dynamic changes in tsMHC-II. Small-animal PET imaging, biodistribution, and histologic studies were performed to validate the correlation of tsMHC-II with the tumor response to the immunotherapy. Results: Fluorescence-activated cell sorting analysis of the 2 tumors supported the consensual recognition of tsMHC-II correlated with 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 nonresponder, B16F10. When treated with anti-PD1 antibody in animals, B16SIY tumors displayed a sensitive increase in tsMHC-II compared with B16F10 tumors. In IFNγ stimulation groups, the greater magnitude of tsMHC-II was further amplified when the IFNγ signaling was activated in the B16SIY tumors, as IFNγ signaling positively upregulates tsMHC-II in the tumor immunity. Subsequent histopathologic 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 versus nonresponders. Monitoring sensitivity of tsMHC-II to IFNγ stimulation may provide an effective strategy to predict the tumor response to immunotherapy.

• Authors: Zhen Yang, Feng Li, Yuqian Huang, Na Yin, Junjun Chu, Ying Ma, Roderic I Pettigrew, Dale J Hamilton, Diego R Martin, Zheng Li
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 63 Issue 11 Pg. 1708-1714 (11 2022) ISSN: 1535-5667 [Electronic] United States
• PMID: 35210298 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 by the Society of Nuclear Medicine and Molecular Imaging.

Chemical References

• Programmed Cell Death 1 Receptor
• Immunologic Factors

Topics

• Animals
• Programmed Cell Death 1 Receptor
• Tissue Distribution
• Immunotherapy (methods)
• Melanoma
• Positron-Emission Tomography (methods)
• Immunologic Factors
• Multiple Myeloma