Effects of localized tumor irradiation on the generation of anti-tumor immunity

Ionizing radiation is an important and commonly used treatment modality for cancer, as it is highly effective at killing large numbers of tumor cells and controlling primary disease. Despite these advantages, radiotherapy is often not a viable option for disseminated metastatic tumors. In contrast immunotherapy, because of its specificity and systemic nature, has the potential to control metastases while limiting bystander toxic effects on normal tissue. Efficacy of immunotherapy for cancer can be improved upon by providing adjuvant signals and an inflammatory tumor microenvironment for immune cell activation. Modulation of the immune response by radiotherapy suggests that it can be successfully combined with immunotherapies for synergistic effects on tumor destruction. The work presented in this thesis is focused on the mechanism by which localized tumor irradiation affects the generation of anti-tumor immune responses. Radiation induced tumor cell death provided a bolus of tumor antigen capable of stimulating specific T cells in the draining lymph node. Upon activation, the T cells were found to infiltrate into irradiated tumors at a greater frequency compared to untreated tumors. Additionally, localized irradiation supported T cell trafficking into the tumor by altering the vasculature and making it more prone to host cell infiltration. Subsequent work examined the role of the inflammatory cytokine interferon-gamma (IFN-gamma) in the phenotype of the irradiated tumor microenvironment. IFN-gamma was found to play an important role in not only the alteration of the tumor vasculature, but also the induction of T cell chemoattractants and expression of major histocompatability complex (MHC) molecules, ligands necessary for T cell recognition of tumor cells. Lastly, the ability of radiotherapy to sustain endogenous anti-tumor responses was examined. The enhancement of T cell responses in the lymph node and within the tumor was short-lived after delivery of a single dose of irradiation. Failure to sustain the high level of immune activation contributed to progressive growth of irradiated tumors. Accumulation of the immunosuppressive cytokine interleukin-10 (IL-10) was observed in treated tumors that had escaped immune control. Neutralization of IL-10 restored the effector function of T cells in the tumor and ablated the immunosuppressive microenvironment through upregulation of pro-inflammatory IFN-gamma. This work has studied the basic mechanisms involved in radiation induced changes to the tumor microenvironment and in the activation of tumor specific T cells, with the ultimate goal of understanding how radiotherapy and immunotherapy can be combined to more effectively treat patients with cancer.