The immune-suppressive tumor microenvironment promotes metastatic spread and outgrowth. One of the major contributors is tumor-associated myeloid cells. However, the molecular mechanisms regulating their differentiation and function are not well understood. Here we report lamin A/C, a nuclear lamina protein associated with chromatin remodeling, was one of the critical regulators in cellular reprogramming of tumorassociated myeloid cells. Using myeloid-specific lamin A/C knockout mice and triplenegative breast cancer (TNBC) mouse models, we discovered that the loss of lamin A/C drives CD11b + Ly6G + granulocytic lineage differentiation, alters the production of inflammatory chemokines, decreases host antitumor immunity, and increases metastasis.The underlying mechanisms involve an increased H3K4me3 leading to the upregulation of transcription factors (TFs) Gfi-1 and C/EBPε. Decreased lamin A/C and increased Gfi-1 and C/EBPε were also found in the granulocytic subset in the peripheral blood of human cancer patients. Our data provide a mechanistic understanding of myeloid lineage differentiation and function in the immune-suppressive microenvironment in TNBC metastasis. K E Y W O R D S granulocytic differentiation, immunosuppression, lamin A/C, metastasis, myeloid cells 1 | INTRODUCTION Distant metastasis is the most common cause of cancer-associated death. 1 In particular, the triple-negative breast cancer (TNBC) subtype has the highest mortality of all breast cancers. 2,3 Patients with TNBC have no targeted therapy and the current treatments are very inefficient. The understanding and targeting of immune checkpoint inhibitors and recent success using adoptive T-cell therapy provide encouraging options that could be applicable in targeting TNBC. 4,5 However, our understanding of the cellular complexity and context-dependent behaviors of the immune microenvironment is limited in TNBC. Moreover, acquired resistance has been a challenge in achieving therapeutic success. 6,7Tumor-associated chronic inflammation promotes a prometastatic microenvironment where certain immune cells are preferentially recruited and suppress cytotoxic T lymphocyte (CTL)-mediated antitumor immunity. 8,9 The majority of prometastatic immune cells are tumor-associated myeloid cells that show apparent functional plasticity, protumor (M2 or N2) or antitumor (M1 or N1) phenotypes. 10,11 These include immature myeloid cells or myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and ---This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
