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SM16 efficacy and radiosensitivity of CT26 and Panc02.

Supplemental Figure legends from TGFβ Inhibition Prior to Hypofractionated Radiation Enhances Efficacy in Preclinical Models

Quantified effect of tumor size and epithelial-to-mesenchymal transition.

The immune infiltrate in colorectal cancer has been correlated with outcome, such that individuals with higher infiltrations of T cells have increased survival independent of the disease stage. For patients with lower immune infiltrates, overall survival is limited. Because the patients with colorectal cancer studied have received conventional cancer therapies, these data may indicate that the pretreatment tumor environment increases the efficacy of treatments such as chemotherapy, surgery, and radiotherapy. This study was designed to test the hypothesis that an improved immune environment in the tumor at the time of treatment will increase the efficacy of radiotherapy. We demonstrate that inhibition of TGFβ using the orally available small-molecule inhibitor SM16 improved the immune environment of tumors in mice and significantly improved the efficacy of subsequent radiotherapy. This effect was not due to changes in radiosensitivity, epithelial–mesenchymal transition, or changes in vascular function in the tumor; rather, this effect was dependent on adaptive immunity and resulted in long-term protective immunity in cured mice. These data demonstrate that immunotherapy is an option to improve the immune status of patients with poor tumor infiltrates and that pretreatment improves the efficacy of radiotherapy. Cancer Immunol Res; 2(10); 1011–22. ©2014 AACR.

We have shown that when studied in isolation, radiation therapy functions poorly as an endogenous vaccine, and that many of the promising therapeutic approaches of radiation in combination with immunotherapy depends on a pre-existing immune response. Therefore, focusing primarily on radiation as an in situ vaccine strategy may yield limited results. We have identified that the ability of radiation therapy to function as a vaccine is dependent on its ability to activate the cDC1 subpopulation of dendritic cells in the tumor and that a lack of endogenous adjuvant and/or active suppression following radiation resulting in lack of maturation of cDC1 may be a major factor that limits control of poorly radioimmunogenic tumors. However, where radiation therapy and immunotherapy combinations work well, radiation therapy cannot be adequately replaced by a potent tumor vaccine, demonstrating that radiation therapy provides critical effects beyond priming new T cell responses. In addition to potential vaccine effects of radiation, it also modifies the cancer cells in the field to make them a better target for control by immune cells. We recently demonstrated that one of the major roles that radiation can play in controlling tumors when combined with immunotherapy is to increase the susceptibility of surviving cancer cells to CD8+ T cells through induction of MHC-I through genetic upregulation of the MHC-I transactivator NLRC5. These data support the critical role of local modulation by radiation in improved tumor control with combination immunotherapy. Citation Format: Marka Crittenden. Integrating radiation therapy with immunotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-013.