Huang, Yuhui

Abstract The clinical success of immune checkpoint inhibitors in treating metastatic and refractory cancers has generated significant interest in investigating their role in treating locally advanced diseases, thus requiring them to be combined with standard treatments in the hope of producing synergistic antitumor responses. Radiotherapy, in particular, has long been hypothesized to have actions complementary to those of immune checkpoint blockade, and a growing body of evidence indicates that cancer immunotherapy may also have radiosensitizing effects, which would provide unique benefit for locoregional treatments. Recent studies have demonstrated that when immune cells are activated by immunotherapeutics, they can reprogram the tumor microenvironment in ways that may potentially increase the radiosensitivity of the tumor. In this review, we highlight the evidence that supports reciprocal interactions between cancer immunotherapy and radiotherapy, where in addition to the traditional notion that radiation serves to enhance the activation of antitumor immunity, an alternative scenario also exists in which T-cell activation by cancer immunotherapy may sensitize tumors to radiation treatment through mechanisms that include normalization of the tumor vasculature and tissue hypoxia. We describe the empirical observations from preclinical models that support such effects and discuss their implications for future research and trial design.

Abstract Solid cancer microenvironment is heterogeneous in nature, comprised of many stromal cell types that work in concert with malignant tumor cells for its maintenance and growth. Among these cell types, tumor-associated macrophages (TAMs) represent a dominant cell population with immunosuppressive and proangiogenic properties. Present in most human cancers, histologic evidence of increased TAMs is often associated with poorer prognosis. Here, we show that the immunosuppressive properties of TAMs can be overcome by modulating tumor microenvironmental parameters. By restoring tumor vascular network and tissue perfusion via anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody, significant reduction of tumor tissue hypoxia and acidosis can be accomplished. Alteration of these local environmental factors directly results in the polarization of TAMs from an immune inhibitory (M2-like) towards immune stimulatory (M1-like) phenotype. In addition, the restoration of aberrant and dysfunctional tumor vessels leads to changes in local cytokine and protein expression profiles that favor the recruitment of immune effector cells, including increased CXCL9 expression. As a result, both CD4+ helper and CD8+ cytotoxic T cell populations were significantly increased within the tumor. Based on these findings, we tested the utility of combining the optimal dose of anti-VEGFR2 antibody therapy with B7-H4 blockade in breast cancer models. Our preliminary data suggests that such treatment enhanced TAM polarization to an anti-tumor phenotype, increased tumor immune cell infiltration and decreased T-cell inhibition, resulting in synergized anti-cancer effects. Therefore, these results suggest that tumor microenvironment modulating therapy provides a new and interesting strategy to augment active immunotherapy for breast as well as other cancer types. Citation Format: Yuhui Huang, Wen Jiang, Betty Y.S. Kim. Tumor microenvironment modulation enhances macrophage polarization and T-cell activation resulting in synergized anti-cancer effect. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3666. doi:10.1158/1538-7445.AM2014-3666