Abstract
Radiation therapy induces immunogenic cell death, which can theoretically stimulate T cell priming and induction of tumor-specific memory T cell responses, serving as an in situ vaccine. In practice, this abscopal effect is rarely observed. We use two mouse models of pancreatic cancer to show that a single dose of stereotactic body radiation therapy (SBRT) synergizes with intratumoral injection of agonistic anti-CD40, resulting in regression of non-treated contralateral tumors and formation of long-term immunologic memory. Long-term survival was not observed when mice received multiple fractions of SBRT, or when TGFβ blockade was combined with SBRT. SBRT and anti-CD40 was so effective at augmenting T cell priming, that memory CD8 T cell responses to both tumor and self-antigens were induced, resulting in vitiligo in long-term survivors.
Highlights
Successful generation of an anti-tumor CD8 T cell response involves multiple steps
Previous reports of fractionated radiation combined with immunotherapy used checkpoint blockade immunotherapies, which act on T cells that infiltrate tumors a week or more after treatment and are temporally protected from the damaging effects of radiation
We hypothesized that multiple fractions of stereotactic body radiation therapy (SBRT) delivered over several days may be detrimental to local dendritic cells which are required for crosspresentation of tumor antigens to naïve CD8 T cells and are likely the cellular targets of anti-CD40 [38]
Summary
Successful generation of an anti-tumor CD8 T cell response involves multiple steps. First, local dendritic cells, laden with antigens from dying tumor cells, become activated and migrate to the draining lymph node [1]. There, activated dendritic cells interact with naïve T cells which become primed, proliferate, and acquire effector capabilities. These activated effector T cells traffic to the tumor, and ideally are able to kill tumor cells via direct cytolysis or production of interferon (IFN)γ. Immunosuppressive myeloid cells in the tumor microenvironment, as well as nutrient starvation and expression of inhibitory ligands such as PD-L1, may prevent CD8 T cell-mediated killing even when CD8 T cell priming has occurred. The fact that immune checkpoint blockade has single-agent efficacy in some cancer patients indicates that CD8 T cell priming successfully occurs in a significant fraction of humans with cancer [2, 3]
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