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

Zhen Yang, Feng Li, Yuqian Huang, Na Yin, Junjun Chu, Ying Ma, Roderic I. Pettigrew, Dale J. Hamilton, Diego R. Martin, Zheng Li

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1708-1714
Number of pages7
JournalJournal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume63
Issue number11
DOIs
StatePublished - Nov 1 2022

Keywords

  • anti-PD1 immunotherapy
  • immuno-PET
  • melanoma
  • MHC-II
  • molecular imaging

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint

Dive into the research topics of 'Dynamic Tumor-Specific MHC-II Immuno-PET Predicts the Efficacy of Checkpoint Inhibitor Immunotherapy in Melanoma'. Together they form a unique fingerprint.

Cite this