Nearly two-thirds of all cancer patients will receive radiation therapy (RT) during treatment, but radiation's curative potential is limited to local-regional disease in either the definitive or adjuvant setting. Locally advanced, unresectable disease represents 30-40% of pancreatic cancer patients at diagnosis and carries a 5- year survival rate of less than 1%. While RT is frequently used and highly effective in metastatic cancer for palliation of symptomatic disease, it has little impact on unirradiated distant sites and thus no impact on survival in the metastatic setting. Likewise in the setting of locally advanced regional disease, such as in pancreatic cancer, radiation is frequently studied in the neoadjuvant setting but with little apparent improvement in overall survival. We have found that radiation therapy activates a myeloid response in the tumor that suppresses adaptive immunity. By targeting the STING (STimulator of INterferon Genes) sensor with cyclic dinucleotides (CDN), we have found that we can prevent suppressive myeloid responses, and when CDN are combined with radiation therapy we can control aggressive murine tumors. We hypothesize that provision of STING ligands in combination with chemoradiation therapy removes the biomarkers of poor response to immunotherapy. We propose that ligation of STING in systemic monocytes that are recruited to tumors following radiation and/or chemotherapy prevents transition to a tumor-promoting environment and enhances tumor associated T cell responses.
The specific aims of this study are to 1: Test the hypothesis that the multicomponent chemoradiation therapy for pancreatic cancer contains core components critical to generate adaptive tumor-specific immune response when combined with systemic STING ligand treatment; 2: Test the hypothesis that the enhanced tumor control provided by systemic STING ligand in combination with radiation therapy and/or chemotherapy results from recruitment of repolarized monocytes to the tumor that in turn promote adaptive immunity in the post-treatment tumor environment; 3: Test the hypothesis that immunotherapies targeting the myeloid compartment via STING ligands will be required for tumors with the biomarkers of poor preexisting immunity and high myeloid involvement. Our study design incorporates preclinical chemoradiation therapy of transplantable and spontaneous models of pancreatic cancer in immune competent mice using an advanced imaging and treatment platform. This proposal particularly focuses on control of both local-regional and distant disease to extend the curative potential of immunotherapy for cancer patients.
Pancreatic tumors have a set of biomarkers that predict that they will be unresponsive to cytotoxic therapy combined with immunotherapies targeting checkpoint inhibitors, specifically: i) low levels of tumor infiltrating T cells; ii) high levels of suppressive myeloid cells; and iii) a tumor environment consisting of unsupportive cytokines and chemokines. We have shown that STING (STimulator of INterferon Genes) ligands can reverse the suppressive tumor environment and generate new T cell responses in a mechanism that is entirely dependent on the targeting capability of cytotoxic therapy. This proposal uses murine models to evaluate STING ligands in the context of conventional chemoradiation therapy for pancreatic cancer to permit effective immune control residual local and distant metastatic disease.
| Crittenden, Marka R; Zebertavage, Lauren; Kramer, Gwen et al. (2018) Tumor cure by radiation therapy and checkpoint inhibitors depends on pre-existing immunity. Sci Rep 8:7012 |
| Tormoen, Garth W; Crittenden, Marka R; Gough, Michael J (2018) Role of the immunosuppressive microenvironment in immunotherapy. Adv Radiat Oncol 3:520-526 |
| Baird, Jason R; Monjazeb, Arta M; Shah, Omid et al. (2017) Stimulating Innate Immunity to Enhance Radiation Therapy-Induced Tumor Control. Int J Radiat Oncol Biol Phys 99:362-373 |
