Combining microenvironment normalization strategies to improve cancer immunotherapy.

Advances in immunotherapy have revolutionized the treatment of multiple cancers. Unfortunately, tumors usually have impaired blood perfusion, which limits the delivery of therapeutics and cytotoxic immune cells to tumors and also results in hypoxia-a hallmark of the abnormal tumor microenvironment (TME)-that causes immunosuppression. We proposed that normalization of TME using antiangiogenic drugs and/or mechanotherapeutics can overcome these challenges. Recently, immunotherapy with checkpoint blockers was shown to effectively induce vascular normalization in some types of cancer. Although these therapeutic approaches have been used in combination in preclinical and clinical studies, their combined effects on TME are not fully understood. To identify strategies for improved immunotherapy, we have developed a mathematical framework that incorporates complex interactions among various types of cancer cells, immune cells, stroma, angiogenic molecules, and the vasculature. Model predictions were compared with the data from five previously reported experimental studies. We found that low doses of antiangiogenic treatment improve immunotherapy when the two treatments are administered sequentially, but that high doses are less efficacious because of excessive vessel pruning and hypoxia. Stroma normalization can further increase the efficacy of immunotherapy, and the benefit is additive when combined with vascular normalization. We conclude that vessel functionality dictates the efficacy of immunotherapy, and thus increased tumor perfusion should be investigated as a predictive biomarker of response to immunotherapy.