18F-FMISO PET Imaging Identifies Hypoxia and Immunosuppressive Tumor Microenvironments and Guides Targeted Evofosfamide Therapy in Tumors Refractory to PD-1 and CTLA-4 Inhibition

Kirsten M. Reeves, Patrick N. Song, Allyson Angermeier, Deborah Della Manna, Yufeng Li, Jianbo Wang, Eddy S. Yang, Anna G. Sorace, Benjamin M. Larimer

Research output: Contribution to journalArticlepeer-review


Purpose: Hypoxia is a common characteristic of many tumor microenvironments, and it has been shown to promote suppression of antitumor immunity. Despite strong biological rationale, longitudinal correlation of hypoxia and response to immunotherapy has not been investigated. Experimental Design: In this study, we probed the tumor and its surrounding microenvironment with 18F-FMISO PET imaging to noninvasively quantify tumor hypoxia in vivo prior to and during PD-1 and CTLA-4 checkpoint blockade in preclinical models of breast and colon cancer. Results: Longitudinal imaging identified hypoxia as an early predictive biomarker of therapeutic response (prior to anatomic changes in tumor volume) with a decreasing standard uptake value (SUV) ratio in tumors that effectively respond to therapy. PET signal correlated with ex vivo markers of tumor immune response including cytokines (IFNg, GZMB, and TNF), damage-associated molecular pattern receptors (TLR2/4), and immune cell populations (macrophages, dendritic cells, and cytotoxic T cells). Responding tumors were marked by increased inflammation that were spatially distinct from hypoxic regions, providing a mechanistic understanding of the immune signaling pathways activated. To exploit image-guided combination therapy, hypoxia signal from PET imaging was used to guide the addition of a hypoxia targeted treatment to nonresponsive tumors, which ultimately provided therapeutic synergy and rescued response as determined by longitudinal changes in tumor volume. Conclusions: The results generated from this work provide an immediately translatable paradigm for measuring and targeting hypoxia to increase response to immune checkpoint therapy and using hypoxia imaging to guide combinatory therapies.

Original languageEnglish
Pages (from-to)327-337
Number of pages11
JournalClinical Cancer Research
Issue number2
StatePublished - Jan 15 2022

Bibliographical note

Funding Information:
The authors thank the UAB Cyclotron Facility, UAB NanoString Core, UAB Pathology Core for technical assistance. Funding was provided by the UAB O’Neal Preclinical Imaging Shared Facility Grant (National Cancer Institute P30CA013148), a NIH Directors’ New Innovator Award (NCI DP2CA261453) to B. Larimer, a NIH Pathway to Independence award (NCI R00CA215604) to B. Larimer, NIH research funding (NCI R01CA240589) to A. Sorace, an American Cancer Society Research Scholar Grant (RSG-18–006–01-CCE) to A. Sorace, and an O’Neal Comprehensive Cancer Center Mary Ann Harvard Award to B. Larimer.

Funding Information:
E.S. Yang reports grants and personal fees from Bayer, grants from Eli Lilly, personal fees from AstraZeneca, and grants and personal fees from Clovis outside the submitted work. A.G. Sorace reports grants from NIH NCI and American Cancer Society during the conduct of the study. B.M. Larimer reports personal fees and other support from Cytosite Biopharma outside the submitted work as well as a patent for Hypoxia PET Imaging to Guide Immunotherapy pending. No disclosures were reported by the other authors.

Publisher Copyright:
© 2021 The Authors; Published by the American Association for Cancer Research.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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