MerTKi与免疫调节性化疗联合治疗可促使三阴性乳腺癌中CXCL9阳性巨噬细胞重编程及抗肿瘤适应性记忆的形成

Breast cancer is the most prevalent cancer and accounts for the second-highest cancer mortality rate in women. Recently, immune checkpoint blockade (ICB) in combination with chemotherapy has become the standard-of-care for Triple-Negative Breast Cancer (TNBC) patients. CD8 T cell infiltration is a predictive marker for ICB and is associated with a better prognosis, whereas suppressive myeloid cell infiltration is associated with a poor prognosis. Tumor-associated macrophages (TAMs) are suppressive myeloid cells that are common targets for solid tumor microenvironment (TME) re-education. While it is known that TAMs orchestrate lymphoid cell activation/inhibition, little is known about TAM programming, derivation, and functionality in tumors. MerTK and Axl (TAMr) are receptor tyrosine kinases expressed by monocytes and TAMs that act as negative regulators of STAT1 signaling in these cells. TAMr inhibition with a MerTKi, MRX-2843, synergizes with Interferon (IFN) to reprogram TAMs in vitro. These reprogrammed cells produce anti-tumor markers such as Cxcl9 and iNOS. Reprogramming of the bone marrow, with immunomodulatory cyclophosphamide drives myeloid cells into the monocytic lineage resulting in increased activated monocyte production. Moreover, IFN signaling is increased within the tumor. When CTX is combined with MRX-2843 long-term durable responses (LTR) are observed in the basal 2153L model, but not in the claudin low T12 model which recurs. Through scRNAseq we identified that IFN signaling maintains lymph activating Mo.Macs that release high levels of Cxcl9 in 2153L. Furthermore, 2153L ‘heats up' early during treatment by Cxcl9 monocytes recruiting both antigen experienced effector CD8 and stem-like memory CD4 T cells to the TME. Importantly, germinal center formation with the tumor draining lymph of combination treated 2153L tumor bearing mice was observed, suggesting that CD4 and B Cell interactions may drive anti-tumor adaptive immunity. In addition, CD8 T Cells express PD-1 and IFN signaling drives PD-L1 expression on monocytes in combination treated mice. The addition of ICB to the CTX + MRX-2843 regimen prevented recurrence in 60% of mice. This study revealed that MRX-2843 synergizes with CTX to drive Cxcl9 and antigen presentation in monocytic cells, resulting in adaptive memory activation via germinal centers. Furthermore, TAM RTK receptors regulate IFN signaling in monocytic derived cells and when inhibited can synergize with chemotherapy to drive long term durable responses in TNBC pre-clinical models. TAM reprogramming with MRX-2843 + CTX + ICB, therefore, may represent a novel therapeutic approach for patients with basal TNBC.