Radiation Effects on the Immune Response to Prostate Cancer

Immunotherapy IT has become popular as an alternative treatment for late-stage and metastatic prostate cancer, however, IT alone is not a very effective modality due to multiple tumor escape mechanisms and would benefit from combination with other therapies, such as Radiation Therapy RT. Our working hypothesis is that while radiation induces danger signals or alarmins in the tumor microenvironment up-regulating co-stimulatory molecules and hence promoting T cell activation, it also affects antigen processing through the proteasome. We believe that radiation also affects antigen presentation by inducing cellular maturation. We observed increases in cell surface markers on irradiated dendritic cells such as MHC II and CD86 in vitro and we were able to show immature dendritic cells appeared to have their propensity to degrade antigen enhanced when they had received radiation prior to antigen exposure. This is important because the state of maturation is in turn known to affect the composition of proteasomes, and hence the antigen repertoire presented. One goal of the proposal is to determine if radiation affects the hierarchy of antigenic peptide presented by DCs and tumor cells. We used murine prostate tumor cells TRAMP but with a human MHC class I molecule, which allowed us to monitor responses to tumor specific antigens that are relevant in the clinical settings. We show that irradiating tumor cells prior to vaccination does not alter their antigenicity. Whether this holds true for local tumor irradiation in vivo will have to be determined. Overall, we conclude from these experiments that the effects of radiation on antigen cross-presentation by dendritic cells in vitro and in vivo are encouraging and give us no reason to believe that radiotherapy is not a good candidate to be used in conjunction with cancer IT, although immune deviation may result in a slightly different response.