Clark et al. used targeted cell deletion genetic approaches and adoptive transfers to understand the mechanism of Treg suppression in breast cancer models. CCR2-mediated bone marrow monocyte recruitment and functional TAM reprogramming were required to achieve a significant antitumor response after Treg cell ablation in vivo. The antitumor effect was dependent on CD4+ T cell-produced INFγ, as a single infusion of monocytes treated ex vivo with IFNγ was sufficient in decreasing tumor burden. Transcriptome signatures of murine TAMs after Treg ablation correlated with increased overall survival in human breast cancer.
Contributed by Katherine Turner
ABSTRACT: Regulatory T (Treg) cell infiltration of solid tumors often correlates with poor prognosis, but their tumor-suppressive function lacks mechanistic understanding. Through a combination of transgenic mice, cell fate mapping, adoptive transfer, and co-injection strategies, we demonstrate that Treg cell ablation-dependent anti-tumor effects in murine breast cancer require intratumoral recruitment of CCR2(+) inflammatory monocytes, which primarily differentiate into tumor-associated macrophages (TAMs), and lead to reprogramming of their function in an IFN-γ-dependent manner. Furthermore, transcriptomic signatures from murine TAMs in Treg cell-ablated conditions correlate with increased overall survival in human breast cancer. Our studies highlight the strong myeloid dependency of breast cancer and provide the basis for the development of therapeutic strategies based on manipulation of the IFN-γ signaling pathway in monocytes.
Author Info: (1) Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; Integrative Life Sciences Graduate Program, Virginia Commonwealth Univers
Author Info: (1) Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; Integrative Life Sciences Graduate Program, Virginia Commonwealth University, Richmond, VA 23298, USA. (2) Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA. (3) Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA. (4) Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA. (5) C. Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA 23298, USA. (6) Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA. (7) Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USA; Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA. (8) Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA. Electronic address: paula.bos@vcuhealth.org.
