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Infiltration of Common Myeloid Progenitor Cells in the Tumor Microenvironment Is Inversely Associated with Cell Proliferation, Better Patient Survival and Response to Immunotherapy in ER-Positive/HER2-Negative Breast Cancer
*Masanori Oshi2, *Kohei Chida1, *Arya M. Roy3, *Li Yan4, *Itaru Endo2, Kazuaki Takabe1
1Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY; 2Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan; 3Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY; 4Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY

Objective: The aim of this study is to investigate the role and clinical relevance of common myeloid progenitor (CMP) cells in the tumor microenvironment (TME) of breast cancer.
Background: There are numerous types of cells in the TME known to promote and/or suppress cancer. However, the roles of cells that are rare in TME are not well studied. Recent technological innovations including in silico transcriptomic analyses have enabled us to capture the roles and clinical relevance of the cells that exist in small quantities in the TME, including CMP.
Methods: In silico analyses were conducted on a total of 5,176 breast cancer patients from large independent cohorts, The Sweden Cancerome Analysis Network-Breast (SCAN-B) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). CMP was identified using xCell algorithm and high CMP patients were defined as those exceeding the median in each cohort.
Results: CMP infiltration rate was significantly higher in smaller tumors, tumors with lower pathological grade, and in ER-positive/HER2-negative breast cancer than in triple-negative breast cancer consistently in both SCAN-B and METABRIC cohorts (all p<0.001). In agreement, high CMP patients were significantly associated with better survival compared to low CMP patients, particularly in ER-positive/HER2-negative breast cancer in both cohorts (overall survival and disease specific survival all p<0.02). ER-positive/HER2-negative breast cancer rich with CMP enriched several pro-cancerous gene sets, including epithelial-to-mesenchymal transition, angiogenesis, hypoxia, coagulation, KRAS signaling, notch signaling, TGF-beta, and myogenesis. On the other hand, low CMP patients significantly enriched all the Hallmark cell proliferation-related gene sets; G2M checkpoint, E2F targets, MYC targets v1, MYC targets v2, and mitotic spindle, as well as MTORC1 signaling, DNA repair, and unfolded protein response. High CMP ER-positive/HER2-negative breast cancer was significantly associated with low fraction of immune cells, including helper T type1 cells, delta-gamma T cells, and regulatory T cells, consistently in both cohorts (all p<0.001). Utilizing the transcriptome of ISPY-2 cohort, we found that CMP infiltration correlated with response to neoadjuvant immune-chemotherapy combination of immune checkpoint inhibitor (durvalumab), PARP inhibitor (olaparib), and paclitaxel for both ER-positive/HER2-negative breast cancer and TNBC (the area under the curve = 0.69 and 0.74, respectively).
Conclusions: In silico approach detects CMPs in the TME and revealed that it is inversely associated with cell-proliferation. CMPs are associated with better patient survival and response to immunotherapy in ER-positive/HER2-negative breast cancer.
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