Divergent response to radio-immunotherapy is defined by intrinsic features of the tumor microenvironment
Authors: Gadwa Jacob , Yu Justin , Piper Miles , Knitz Michael W. , Darragh Laurel B. , Olimpo Nicholas A. , Corbo Sophia , Neupert Brooke , Beynor Jessica I. , Nguyen Alexander , Hodgson Chloe , Abdelazeem Khalid N.M. , Nguyen Diemmy , Saviola Anthony J. , Pincha Mudita , Klein Christian , Amann Maria , Karam Sana D. 
Published: September 2024

AbstractBackgroundTreatment 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.MethodsUsing combinatorial radio-immunotherapy consisting of PD-1 blockade, IL2Rβγ biased signaling, and OX40 agonism we were able to generate preclinical tumor models with conflicting responses, where head and neck squamous cell carcinoma (HNSCC) models responds and pancreatic ductal adenocarcinoma (PDAC) progresses.ResultsBy modeling these disparate states, we find that regulatory T cells (Tregs) are expanded in PDAC tumors undergoing treatment, constraining tumor reactive CD8 T cell activity. Consequently, the depletion of Tregs restores the therapeutic efficacy of our treatment and abrogates the disparity between models. Moreover, we show that through heterotopic implantations that the site of tumor development defines the response to therapy, as implantation of HNSCC tumors into the pancreas resulted in comparable levels of tumor progression.ConclusionsThis work highlights complexity of combining immunotherapies within the tumor microenvironment and further defines the immune and non-immune components of the tumor microenvironment as an intrinsic feature of immune suppression.What is already known on this topicIn 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. The T cell co-stimulatory receptor OX40 (TNFRSF4) has pleiotropic effects, promoting T cell survival, expansion, and memory differentiation in conventional effector T cells, while subsequently limiting regulatory T cell (Treg) suppression by constraining induction and expression of Foxp3. Expression of 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.What this study addsUsing orthotopic models of HNSCC and PDAC, we found that the addition of OX40 agonism unexpectedly drives tumor progression in PDAC, but not HNSCC. Intriguingly, this effect dependent on the tumor microenvironment as the effect is reversed by swapping the location of tumor implantation. This progression was also abrogated by the depletion of regulatory T cells (Tregs), a known mediator of resistance in these models.How this study might affect research, practice or policyOur data demonstrate that unexpected and deleterious effects can stem from combining multiple immunotherapies. These findings hold particular translational relevance as the use of combination immunotherapies is increasingly common on trial.