RESUMO
CONTEXT: Hypoxia within the tumor microenvironment is a critical factor influencing the efficacy of immunotherapy, including immune checkpoint inhibition. Insufficient oxygen supply, characteristic of hypoxia, has been recognized as a central determinant in the progression of various cancers. The reemergence of evofosfamide, a hypoxia-activated prodrug, as a potential treatment strategy has sparked interest in addressing the role of hypoxia in immunotherapy response. This investigation sought to understand the kinetics and heterogeneity of tumor hypoxia and their implications in affecting responses to immunotherapeutic interventions with and without evofosfamide. PURPOSE: This study aimed to investigate the influence of hypoxia on immune checkpoint inhibition, evofosfamide monotherapy, and their combination on colorectal cancer (CRC). Employing positron emission tomography (PET) imaging, we developed novel analytical methods to quantify and characterize tumor hypoxia severity and distribution. PROCEDURES: Murine CRC models were longitudinally imaged with [18F]-fluoromisonidazole (FMISO)-PET to quantify tumor hypoxia during checkpoint blockade (anti-CTLA-4 + and anti-PD1 +/- evofosfamide). Metrics including maximum tumor [18F]FMISO uptake (FMISOmax) and mean tumor [18F]FMISO uptake (FMISOmean) were quantified and compared with normal muscle tissue (average muscle FMISO uptake (mAvg) and muscle standard deviation (mSD)). Histogram distributions were used to evaluate heterogeneity of tumor hypoxia. FINDINGS: Severe hypoxia significantly impeded immunotherapy effectiveness consistent with an immunosuppressive microenvironment. Hypoxia-specific PET imaging revealed a striking degree of spatial heterogeneity in tumor hypoxia, with some regions exhibiting significantly more severe hypoxia than others. The study identified FMISOmax as a robust predictor of immunotherapy response, emphasizing the impact of localized severe hypoxia on tumor volume control during therapy. Interestingly, evofosfamide did not directly reduce hypoxia but markedly improved the response to immunotherapy, uncovering an alternative mechanism for its efficacy. CONCLUSIONS: These results enhance our comprehension of the interplay between hypoxia and immune checkpoint inhibition within the tumor microenvironment, offering crucial insights for the development of personalized cancer treatment strategies. Non-invasive hypoxia quantification through molecular imaging evaluating hypoxia severity may be an effective tool in guiding treatment planning, predicting therapy response, and ultimately improving patient outcomes across diverse cancer types and tumor microenvironments. It sets the stage for the translation of these findings into clinical practice, facilitating the optimization of immunotherapy regimens by addressing tumor hypoxia and thereby enhancing the efficacy of cancer treatments.
