Divergent response to radio-immunotherapy is defined by intrinsic features of the tumor microenvironment 9052

Description Treatment with immunotherapy can elicit varying responses across cancer types, and the mechanistic underpinnings that contribute to response vs. progression remain poorly understood. However, to date there are few preclinical models that accurately represent these disparate disease scenarios. In head and neck squamous cell carcinomas (HNSCC) and pancreatic ductal adenocarcinoma (PDAC), targeting PD-1 and IL2Rβγ simultaneously (PD1-IL2v) has been shown to be effective when combined with radiation therapy (RT), yet complete response is still limited. Expression of the T cell co-stimulatory receptor OX40 is highly upregulated after treatment with PD1-IL2v, and we postulated that combining OX40 agonism with PD1-IL2v and RT would provide additional benefit. Using orthotopic models of HNSCC and PDAC, we found that OX40 agonism unexpectedly drives tumor progression in PDAC, but not HNSCC, when combined with RT and PD1-IL2v. Intriguingly, this effect appears dependent on the tumor microenvironment as the effect is reversed by swapping the location of tumor implantation. This progression was subesquently abrogated by the depletion of regulatory T cells (Tregs), a known mediator of resistance in these models, implicating Tregs as a mechanistic denominator behind this progression. Importantly, in an age where combining immunotherapies is increasingly common on trial, our data demonstrate that unexpected and deleterious effects can stem from combining multiple immunotherapies. Funding Sources Sana D. Karam is funded by the following grants: R01DE028529, R01CA28465, R01DE028282, 1P50CA261605-01, V Foundation, and the Wings of Hope Foundation for Pancreatic Cancer Research. Jacob Gadwa is funded by the following grant: F31 DE033887-01. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)