Abstract IA23: Impact of metastatic prostate cancer on human bone marrow

Cancer-related mortality due to solid tumor malignancies is overwhelmingly due to the development and progression of metastases. In advanced prostate cancer, metastases most often involve the bone and generally represent incurable disease. It remains unclear what aspects of the bone marrow microenvironment make it hospitable to metastatic dissemination. Similarly, the impact of the metastatic tumor on hematopoiesis and the marrow immune response is poorly understood. We took advantage of rare spinal cord decompression surgeries to profile marrow and metastatic tumors from men with advanced prostate cancer at single-cell resolution. Our analysis contrasts the cellular composition and transcriptional states in matched samples of tumor and liquid bone marrow collected at adjacent vertebral body levels, as well as bone marrow of orthopedic patients without malignancy. Metastatic prostate cancer was associated with hematopoietic suppression and multifaceted immune distortion. There was exhaustion of specific T cell subsets, appearance of inflammatory monocytes and macrophages, and alteration of cytokine profiles. Computational analysis showed association between the presence of specific myeloid subsets and the level of T lymphocyte dysfunction in the tumor fraction. We screened for potential signaling axes that may underlie this interaction. Among them was chemokine CCL20, notably overexpressed by myeloid cells, as was its cognate CCR6 receptor, expressed on T cells. We developed a syngeneic mouse model of bone-metastatic prostate cancer to explore this observation, and demonstrated that disruption of the CCL20-CCR6 axis from either side resulted in significant prolongation of survival. Our results further indicated that this dual overexpression was associated with repressed immune responses. Overall, comparative high-resolution analysis of bone marrow reveals distinct alterations associated with prostate cancer bone metastases that may be amenable to therapeutic targeting with the goal of altering cancer progression. Citation Format: Ninib Baryawno, Youmna Kfoury, Nicolas Severe, Shenglin Mei, Karin Gustafsson, Taghreed Hirz, Thomas Brouse, Elizabeth W. Scadden, Anna A. Igolkina, Bryan D. Choi, Nikolas Barkas, John H. Shin, Philip J. Saylor, David T. Scadden, David B. Sykes, Peter V. Kharchenko, as part of the Boston Bone Metastasis Consortium. Impact of metastatic prostate cancer on human bone marrow [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA23.