Divergent response to radio-immunotherapy in HNSCC and PDAC is mediated by regulatory T cells

Abstract public domain (NIH RePORTER)

Abstract Head and neck squamous cell carcinoma (HNSCC) and pancreatic adenocarcinoma (PDAC) differ in many of the genetic drivers, low responsiveness to immunotherapy remains a commonality shared between both. Resistance to therapy remains an issue and while the field awaits results from numerous ongoing clinical trials, the mechanistic underpinnings that contribute to response vs. progression remain poorly understood. Our lab has shown that radiation therapy (RT) and PD1-IL2v, an immunocytokine that selectively delivers IL2 to PD-1 expressing cells via the intermediate affinity IL-2Rβγ, promotes increased infiltration, activation, and cytotoxicity of CD8 T cells and natural killer (NK) cells in preclinical orthotopic models of HNSCC and PDAC. Although the effect is substantial and results in significant tumor regression and abrogation of metastasis, the effect is transient, and tumors reoccur in the majority of mice. We therefore sought to investigate additional immunotherapies that can be added to further sustain the anti-tumor immune response induced by RT + PD1- IL2v. OX40 is a secondary costimulatory receptor which is expressed on activated T cells and provides survival signals which are critical to maintain long term immune responses. OX40 agonism has been shown to synergize well with immune checkpoint blockade (ICB), effectively boosting anti-tumor immunity in multiple tumor models. OX40 therefore represented a suitable candidate for combinatorial therapy along with PD1-IL2v and RT. Upon the addition of αOX40, we observed a striking dichotomy in the responses between preclinical models of HNSCC and PDAC. αOX40 promotes further efficacy of RT + PD1-IL2v and drives tumor eradication in HNSCC, whereas survival is significantly decreased in PDAC compared to RT + PD1-IL2v. Regulatory T cells (Tregs), have been established as critical mediators of response in both HNSCC and PDAC, and interestingly, the depletion of Tregs re-establishes to therapy. Delving deeper into this disparity, we observed that PDAC tumor microenvironment (TME) have an increased abundance of the cytokine IL-33 and is enriched with Tregs expressing the IL-33 receptor ST2, a distinctly suppressive subset which is associated with tumor progression. We therefore hypothesize that OX40 agonism drives accelerated tumor progression in PDAC by preferentially activating ST2 expressing Tregs in the PDAC TME. Aim 1 will focus on the effect that deletion of OX40 from Tregs has on therapeutic outcomes in the context of RT + PD1-IL2v + αOX40. In Aim 2, we will explore the tumor and TME intrinsic factors that can influence the dichotomous response to our combined radio-immunotherapy. We expect that this proposal will provide a mechanistic understanding of the parameters that determine response vs. progression.

Public health relevance public domain (NIH RePORTER)

Narrative Head and neck cancer (HNSCC) and pancreatic ductal adenocarcinoma (PDAC) exhibit dichotomous responses to combination radiation immunotherapy in the context of OX40 agonism, highlighted by decreased CD8 T cell effector function and enhanced regulatory T cell (Treg) suppression, resulting in diminished survival in PDAC models. The PDAC tumor microenvironment (TME) is rich in IL-33 and Tregs which express the cognate receptor ST2. We aim to determine the differential responses to OX40 agonism between HNSCC and PDAC, and whether the IL-33/ST2 axis on Tregs promotes a suppressive TME.