In clinically relevant GEMM models, Kos et al. investigated the effects of primary mammary tumorigenesis on Tregs in distant organs to determine if tumor-educated Tregs influence metastases in tissue-dependent ways. Primary tumor formation resulted in systemic expansion and activation of highly immunosuppressive Tregs, which selectively promoted metastases in axial lymph nodes (LN), but not in the lungs, through local suppression of NK cells only in the LN niche. An increased Treg/NK cell ratio was also observed in sentinel LNs from human breast cancer patients. Thus, immune control of metastatic disease may be highly organ-dependent.
Contributed by Katherine Turner
ABSTRACT: Breast cancer is accompanied by systemic immunosuppression, which facilitates metastasis formation, but how this shapes organotropism of metastasis is poorly understood. Here, we investigate the impact of mammary tumorigenesis on regulatory T cells (T(regs)) in distant organs and how this affects multi-organ metastatic disease. Using a preclinical mouse mammary tumor model that recapitulates human metastatic breast cancer, we observe systemic accumulation of activated, highly immunosuppressive T(regs) during primary tumor growth. Tumor-educated T(regs) show tissue-specific transcriptional rewiring in response to mammary tumorigenesis. This has functional consequences for organotropism of metastasis, as T(reg) depletion reduces metastasis to tumor-draining lymph nodes, but not to lungs. Mechanistically, we find that T(regs) control natural killer (NK) cell activation in lymph nodes, thereby facilitating lymph node metastasis. In line, an increased T(reg)/NK cell ratio is observed in sentinel lymph nodes of breast cancer patients compared with healthy controls. This study highlights that immune regulation of metastatic disease is highly organ dependent.
Author Info: (1) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (2) Division of Tumor Biol
Author Info: (1) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (2) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan 60800, Pakistan. (3) Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam and Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, the Netherlands. (4) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (5) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands. (6) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (7) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (8) Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam and Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, the Netherlands. (9) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (10) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (11) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (12) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (13) Cancer Immunology Unit, University College London Cancer Institute, WC1E 6DD London, UK. (14) Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, VIB, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. (15) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands. (16) Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam and Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, the Netherlands. (17) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: k.d.visser@nki.nl.
