The role of ionizing radiation as an ?in situ? vaccine is based on radiation?s ability to induce the release of tumor antigens which activate antigen-presenting cells to prime CD8+ T cells. This mediates the ?abscopal effect? in which radiation to one tumor leads to eradication of a distant tumor. However, clinical reports of the ?abscopal effect? are rare, possibly because radiation can promote the generation of immunosuppressive cells. While radiation has been used therapeutically for over a century, it is still poorly understood which types of cell death are induced by different types of radiation regimens and how these mechanisms of cell death effect the inflammatory milieu and anti-tumor immunity. Interestingly, while T cells are very sensitive to apoptosis, but tissue-resident innate lymphoid cells (ILC) are radioresistant. Group 1, 2 and 3 ILCs are activated by specific members of the IL-1 family of cytokines which serve as ?alarmins? of tissue damage. However, the precise contribution of cell death to IL-1 cytokine release and downstream immune responses has not been well characterized, and ILC have never been implicated in the immune response to radiation. Therefore, the proposed experiments will address critical gaps by examining how radiotherapy-induced mechanisms of cell death release specific IL-1 family cytokines in the tumor micorenvironment to activate various ILC subsets (Aim 1). The K99 mentored experiments will involve the integration of patient derived organoids, cell death assays, and novel orthotopic murine tumor models, as well as knockout mice for various cytokines. Results from Aim 1 will lead to subsequent R00 independent phase investigations to determine how radiation-induced immune responses regulate the balance between anti-tumor immunity (Aim 2) and radiation-induced pneumonitis and fibrosis (Aim 3).
Aim 3 will build on my doctoral work generating the IL-22-IRES-BFP reporter mouse to study the role of this ILC3-induced cytokine in radiation-induced fibrosis. Collectively, the research will yield unprecedented insight into how radiation-induced cell death mechanisms and specific cytokines direct downstream immune responses and clinical outcomes. The technical training and career development obtained during the R99 phase will help me to launch my independent research program and reveal additional questions for future investigation. Results from this work will serve as preliminary data for a translational study to investigate if there is a correlation between radiation-induced cell death, release of IL-1 cytokine family members, immune cell activation, and clinical outcomes. Given my comprehensive training and experience in both immunology and radiation oncology, I am uniquely positioned to utilize both skillsets to address important questions at the intersection of these fields and gain fundamental understanding of the mechanisms that underlie the efficacy of radiation therapy.
Recent clinical trials have added radiation therapy to immune checkpoint inhibitors based on the dogma that radiation releases antigens that?s activates dendritic cells and primes CD8+ T cell responses to result in an abscopal response. However, these abscopal responses are rarely seen, perhaps due to radiation-dependent lymphocyte apoptosis. The critical knowledge gap is how different forms of radiation-induced cell death induce both anti-tumor immunity and side effects from radiation; the proposed work will inform future development of immunotherapies and radiation therapy synergy.
