It has been well-established that patients with PTEN deficiency have poor prostate cancer outcomes. Dr. Alimonti remarks that in PTEN null mice, myeloid cells are enriched in the prostate tumor microenvironment. Indeed, prostate cancer patients have increased tumor and circulating levels of myeloid-derived suppressor cells already at the time of diagnosis. Myeloid-derived suppressor cells are mobilized from the bone marrow of affected patients and recruited to the tumor microenvironment through a complex pathway regulated by CCLs and CXCLs. Furthermore, Gr-1+ myeloid cells support prostate cell proliferation and tumor-infiltrating Gr-1+ myeloid cells support prostate cancer progression. On the contrary, impaired recruitment of Gr-1+ cells enhances chemotherapy-induced senescence. Subsequently, targeting tumor-infiltrating myeloid-derived suppressor cells has become an increased area of research interest. As such, preliminary work suggests that myeloid-derived suppressor cell targeted therapies enhance the efficacy of checkpoint inhibitors in patients with mCRPC.
Myeloid-derived suppressor cells play a number of roles in cancer progression and treatment resistance, including (i) assisting with angiogenesis, (ii) assisting with tissue remodeling, (iii) suppression of specific T-cell immunity, and (iv) hindering senescence induction in tumor cells. Submitted work from Dr. Alimonti’s labs also suggest that myeloid-derived suppressor cells expand in prostate tumors upon development of castration, continue infiltrating the tumor, and promote androgen resistance in the tumor microenvironment.
Dr. Alimonti also discussed the importance of tumor-associated macrophages, noting that both mouse and human prostate cancers are heavily infiltrated. Tumor-associated macrophages are plastic cells that can be shaped by the tumor microenvironment in different subsets. As presented earlier this week at ESMO 2017, tumor-associated macrophage reprogramming is more efficient than tumor-associated macrophage killing . Specifically, tumor-associated macrophages can be reprogrammed by treatment with CXCR2 antagonists; adoptive transfer of alpha CXCR2-depleted monocytes drives tumor-associated macrophage re-education in PTEN/p53 tumors.
Dr. Alimonti concluded his presentation by highlighting that myeloid-derived suppressor cells and tumor-associated macrophages are the major immune subsets infiltrating prostate tumor cells at different stages of the disease and can promote the emergence of CRPC through different mechanisms. Therapies that block myeloid-derived suppressor cells or reprogram tumor-associated macrophages may provide additional avenues for treating patients with CRPC.
Speaker: Andrea Alimonti, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain
1. Di Mitri D, Vasilevska J, Calcinotto A, et al. Re-education of tumor-associated macrophages by CXCR2 blockade drives senescence enhancement and tumor inhibition in advanced prostate cancer. ESMO 2017 abstr 791.