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Principal Investigator: Jacob Gadwa
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2024
Award: $37,384
Funding agency: National Institute of Dental and Craniofacial Research
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.
Terms: <Ablation><Acceleration><Address><Affinity><After Care><After-Treatment><Aftercare><Aldesleukin Gene><Antitumor Response><Assay><Bioassay><Biological Assay><CD134><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancer Model><Cancer Treatment><CancerModel><Cell Body><Cell Communication and Signaling><Cell Function><Cell Line><Cell Physiology><Cell Process><Cell Signaling><Cell-Mediated Lympholytic Cells><CellLine><Cells><Cellular Function><Cellular Physiology><Cellular Process><Characteristics><Clinical><Clinical Trials><Co-Stimulator><Combination immunotherapy><Costimulator><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Cytotoxic cell><Data><Disparities><Disparity><Ductal Carcinoma of the Pancreas><Epidermal Thymocyte Activating Factor><Exhibits><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Future><GEM model><GEMM model><Gene Expression><Genetic><Genetically Engineered Mouse><HNSCC><Head and Neck Cancer><Head and Neck Carcinoma><Head and Neck Squamous Cell Carcinoma><IL-2><IL-2 Gene><IL2><IL2 Protein><IL2 gene><Immune><Immune mediated therapy><Immune response><Immunes><Immunological response><Immunologically Directed Therapy><Immunoradiotherapy><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Implant><Infiltration><Inflammatory><Interleukin 2><Interleukin 2 Precursor><Interleukin 2 Precursor Gene><Interleukin II><Interleukin-2><Interleukin-2 Gene><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intracellular Communication and Signaling><Intrinsic factor><K lymphocyte><Lymphocyte Mitogenic Factor><Lytotoxicity><Malignant Head and Neck Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Mediating><Mediator><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Mitogenic Factor><Modeling><Murine><Mus><NK Cells><Natural Killer Cells><Neoplasm Metastasis><OX40><PD 1><PD-1><PD1><Pancreas Adenocarcinoma><Pancreas Duct-Cell Carcinoma><Pancreas Ductal Adenocarcinoma><Pancreatic Adenocarcinoma><Pancreatic Duct Cell Carcinoma><Pancreatic Ductal Adenocarcinoma><Pancreatic Ductal Carcinoma><Patients><Phenotype><Population><Pre-Clinical Model><Preclinical Models><Principal Investigator><Publishing><RNA Seq><RNA sequencing><RNAseq><Radiation><Radiation therapy><Radioimmunotherapy><Radiotherapeutics><Radiotherapy><Receptor Protein><Regimen><Regulatory T-Lymphocyte><Resistance><SCCHN><Sampling><Secondary Neoplasm><Secondary Tumor><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Site><Spinal Column><Spine><Strains Cell Lines><Subcellular Process><T cell growth factor><T-Cell Activation><T-Cell Growth Factor><T-Cell Growth Factor Gene><T-Cell Stimulating Factor><T8 Cells><T8 Lymphocytes><TCGF Gene><Teff cell><Testing><Therapeutic><Thymocyte Stimulating Factor><Treg><Tumor Burden><Tumor Immunity><Tumor Load><Tumor-Derived><Vertebral column><activate T cells><anti-cancer therapy><anti-tumor immune response><anti-tumor immunity><anti-tumor response><antitumor immunity><backbone><biological signal transduction><cancer immunity><cancer metastasis><cancer microenvironment><cancer progression><cancer therapy><cancer type><cancer-directed therapy><career><check point blockade><checkpoint blockade><combinatorial><combinatorial immunotherapy><cultured cell line><cytokine><cytotoxicity><dual immunotherapy><effector T cell><experiment><experimental research><experimental study><experiments><flow cytophotometry><genetically engineered mouse model><genetically engineered murine model><head and neck squamous carcinoma><head and neck squamous cell cancer><head/neck cancer><host response><immune check point><immune check point blockade><immune checkpoint><immune checkpoint blockade><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immunecheckpoint><immuno therapy><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><in vivo><inhibitor><killer T cell><malignant head and neck tumor><neoplasm progression><neoplastic progression><pharmacologic><post treatment><pre-clinical><preclinical><programmed cell death 1><programmed cell death protein 1><programmed death 1><radiation treatment><receptor><regulatory T-cells><resistance to therapy><resistant><resistant to therapy><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><sle2><success><synergism><systemic lupus erythematosus susceptibility 2><therapeutic outcome><therapeutic resistance><therapy outcome><therapy resistant><transcriptome sequencing><transcriptomic sequencing><treatment resistance><treatment with radiation><trial design><tumor><tumor cell metastasis><tumor eradication><tumor growth><tumor microenvironment><tumor progression>