Abstract 4988: Reprogramming the immunologic microenvironment through radiation and Axl targeting

Abstract

There is increasing evidence that hypofractionated high dose ionizing radiation (RT) can enhance antitumor immune responses in many cancers. In some cases the combination of RT and checkpoint immunotherapy can enhance antitumor immune responses. Here, we developed a model to study the genetic, microenvironmental, and immunologic factors of immune mediated antitumor responses after radiation. Two different tumor clones from the same parental transgenic PyMT mammary carcinoma model reveal similar growth characteristics but different responses to RT primarily due to an antitumor immune response. The responsive Py117 tumors increase expression of PD-L1 after RT and the antitumor response is enhanced with immune checkpoint antibodies (Ab) targeting PD-1 and CTLA-4. However the unresponsive Py8119 tumors do not respond to radiation or combination immunotherapy. Key differences in the microenvironment include greater infiltration of suppressive macrophages, lower MHCI on tumor cells, and low T cell infiltrates. Upon profiling differences in the tumors we found that Axl a receptor tyrosine kinase of the TAM family associated with invasion and metastasis in a broad range of tumors was overexpressed on the surface of Py8119 cells but not Py117. We genetically knocked out Axl in Py8119 cells using CRISPR/Cas technology and found greater tumor latency and enhanced radiosensitivity in the mouse but not in culture. The effects are largely immune mediated as the RT response was diminished in nude mice. On analysis of the tumor cells we found that MHCI is significantly increased and secretion of a number of chemokines is diminished after Axl targeting. In the tumor microenvironment there was significant decrease in macrophages, increase in myeloid dendritic cells, and resulting influx of T cells by 10 days after RT. These data suggest that Axl may not only mediate invasion and metastasis but can influence immunoserveilance and response to therapy through suppression of antigen presentation and supporting a tumor promoting immune microenvironment through chemokine signaling.

Citation Format: Todd A. Aguilera, Marjan R. Rafat, Laura Castellini, Mihalis S. Kariolis, Rie vonEbyen, Edward E. Graves, Amato J. Giaccia. Reprogramming the immunologic microenvironment through radiation and Axl targeting. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4988.