Immune Modulation by Androgen Deprivation and Radiation Therapy: Implications for Prostate Cancer Immunotherapy

Abstract

Prostate cancer patients often receive androgen deprivation therapy (ADT) in combination with radiation therapy (RT). Recent evidence suggests that both ADT and RT have immune modulatory properties. First, ADT can cause infiltration of lymphocytes into the prostate, although it remains unclear whether the influx of lymphocytes is beneficial, particularly with the advent of new classes of androgen blockers. Second, in rare cases, radiation can elicit immune responses that mediate regression of metastatic lesions lying outside the field of radiation, a phenomenon known as the abscopal response. In light of these findings, there is emerging interest in exploiting any potential synergy between ADT, RT, and immunotherapy. Here, we provide a comprehensive review of the rationale behind combining immunotherapy with ADT and RT for the treatment of prostate cancer, including an examination of the current clinical trials that employ this combination. The reported outcomes of several trials demonstrate the promise of this combination strategy; however, further scrutiny is needed to elucidate how these standard therapies interact with immune modulators. In addition, we discuss the importance of synchronizing immune modulation relative to ADT and RT, and provide insight into elements that may impact the ability to achieve maximum synergy between these treatments.

Impact of curative radiotherapy on the immune status of patients with localized prostate cancer

“…Several clinical trials with combination regimens are ongoing. 52 In contrast to these and our data, radio (chemo)therapy for cervical cancer induced a profound and long lasting (up to 9 weeks after treatment completion) decrease in CD4 + and CD8 + T cell subsets, but not in Tregs, hence does not seem promising for combination with immunotherapy. 53 Thus, it is important to test the effects of RT on the immune system in each clinical setting considered for combination of radio(chemo)therapy and immunotherapy.…”

Cancer‑related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction

“…The synergistic effect of AdT and RT is likely related to the role of AdT as a 'radiosensitizer' by downregulating dNA repair genes, thus accelerating dNA damage induced by RT (12)(13)(14). Alternatively, an enhanced immune response has been suggested as another possible mechanism of the synergistic effect of AdT and RT (15,16). Despite these benefits, treatment with ADT can result in a multitude of iatrogenic conditions including increased risk for diabetes, cardiovascular diseases, sexual health dysfunction, depression, cognitive and mood dysfunction (11,17).…”

Targeting prostate cancer stem-like cells by an immunotherapeutic platform based on immunogenic peptide-sensitized dendritic cells-cytokine-induced killer cells

“…On the other hand, the immune environment in primary tumors of prostate cancer can be modulated by therapies. It is shown that ADT can enhance the accumulation of T lymphocytes (CD3 + , CD8 + ) and CD68 + macrophages and thus induce some short-term beneficial immune responses [56,57]. This also provides the rationale that the combination of immunotherapy with ADT may offer additional or synergistic efficacy in the treatment of prostate cancer.…”