Abstract PO-048: VISTA immune-checkpoint blunts radiotherapy induced anti-tumor immune response
Authors: Nambiar Dhanya K. , Mehta Nishant , Maddineni Sainiteesh , Cao Hongbin , Viswanathan Vignesh , Cheunkarndee Tia , Cochran Jennifer R. , Le Quynh Thu 
Published: April 2021

Abstract
Radiotherapy (RT) is the primary treatment of many solid neoplasms including head and neck cancer (HNC). Itis well accepted that the tumoricidal effects of RT can be significantly influenced by the immune system. Induction of cell death by radiation can elicit an anti-tumor immune response; however, it could also promote pathways of immunosuppression, which in turn can stimulate local tumor recurrence and/or distant metastases. A mechanism by which RT or chemoradiation (CRT) contributes to immunosuppression is by expansion of myeloid derived suppressive cells (MDSCs). MDSCs are a heterogeneous population of immature myeloid cells, which undergo significant expansion during cancer development and progression. Although MDSCs have been linked to inferior prognosis and treatment failure, the mechanisms by which they contribute to treatment RT failure are not well understood. Through this study we investigated the role of VISTA (V-domain Ig Suppressor of T cell Activation) immune-checkpoint on MDSCs in regulating RT response in vivo. Using syngeneic mouse models of HNC (MOC2 [HPV-] & MEERL [HPV+]), we show that both single fraction/fractionated irradiation regimens significantly increase polymorphonuclear (PMN)-MDSCs in both the tumor and the blood post-RT. We see a similar increase in PMN-MDSCs in HNC patient blood samples (12/16) at mid treatment time point (3-4 weeks after starting RT). Further analyses of immune cells reveal a significant induction of the inhibitory immune-checkpoint VISTA on PMN-MDSCs post-RT. VISTA is a multifaceted negative checkpoint protein that is expressed on most hematopoietic cells, especially on myeloid lineage. VISTA is known to contribute to the overall T cell-suppressive function. We find that irradiation of bone marrow derived-MDSCs or patient PBMC derived PMN-MDSCs leads to upregulation of VISTA surface expression as early as 24 hours after RT. Additionally, the VISTAhi MDSCs have significantly elevated levels of the immunosuppressive cytokine IL-10. We then seek to study the impact of inhibiting VISTA on RT induced immune response and tumor control in a HNC model. The combination of anti-VISTA antibody and fractionated RT (3Gy X 5) leads to a significant decrease in tumor volume compared to either RT alone or anti-VISTA antibody alone. Therapeutic blocking of VISTA checkpoint along with radiation also lead to a reduction in metastatic seeding in the lung in these mice compared to RT alone group. These findings are associated with a decrease of PMN-MDSCs in both tumor and the lungs and an increase in CD4+ T cells and dendritic cells in the tumor of the anti-VISTA antibody + RT group compared to RT alone group. These results underline the role of VISTA in compromising the anti-tumor effects of RT and suggest that targeting VISTA may enhance RT efficacy in HNC patients.
Citation Format: Dhanya K. Nambiar, Nishant Mehta, Sainiteesh Maddineni, Hongbin Cao, Vignesh Viswanathan, Tia Cheunkarndee, Jennifer R. Cochran, Quynh Thu Le. VISTA immune-checkpoint blunts radiotherapy induced anti-tumor immune response [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 PO-048.