Lamorte et al. investigated the role of medullary sinus macrophages (MSMs) in tumor-draining lymph nodes (TDLNs) in regulating mechanisms of cancer therapy resistance. Phagocytosis of murine apoptotic tumor debris by MSMs induced IL-33 expression, resulting in Treg activation in the TDLNs, migration to the tumor, and suppression of CD8+ T cell-mediated antitumor immunity. When combined with chemotherapy or a targeted TKI, IL-33 inhibition enhanced antitumor efficacy, which was further improved with PD-1 blockade. In patients with melanoma, low IL-33 expression and a destabilized Treg signature in sentinel LNs correlated with disease stage and improved survival.
Contributed by Katherine Turner
ABSTRACT: Apoptotic cells are immunosuppressive, creating a barrier in cancer treatment. Thus, we investigated immune responses to dying tumor cells after therapy in the tumor draining lymph node (TDLN). A key population responsible for clearing tumor material in the TDLN was medullary sinus macrophages (MSMs). Tumor debris phagocytosis by MSMs induces the cytokine IL-33, and blocking the IL-33 receptor (ST2) or deletion of Il33 in MSMs enhances therapy responses. Mechanistically, IL-33 activates T regulatory cells in TDLNs that migrate to the tumor to suppress CD8(+) T cells. Therapeutically combining ST2 blockade, targeted kinase inhibitors, and anti-PD-1 immunotherapy increases CD8(+) T cell activity promoting tumor regression. Importantly, we observe similar activity in human macrophages, and IL-33 expression in sentinel lymph nodes correlates with disease stage and survival in melanoma. Thus, our data identifies an IL-33-dependent immune response to therapy that attenuates therapy-induced anti-tumor immunity.
Author Info: (1) Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada. (2) Princess Margaret Cancer Cen
Author Info: (1) Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada. (2) Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada. (3) Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada. (4) Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada. (5) Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada. (6) Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada. (7) Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada. (8) Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, The University of Toronto, Toronto, ON, Canada. (9) Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. (10) Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada. (11) Department of Laboratory Medicine and Pathobiology, The University of Toronto, Toronto, ON, Canada. (12) Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Laboratory Medicine and Pathobiology, The University of Toronto, Toronto, ON, Canada. (13) Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada. (14) Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, The University of Toronto, Toronto, ON, Canada. (15) Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Medical Biophysics, The University of Toronto, Toronto, ON M5S 1A8, Canada. (16) Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA. (17) Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. (18) Department of Microbiology, Tumor, and Cell Biology, The Karolinska Institute, 171 77 Stockholm, Sweden. (19) Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada. (20) Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: tracy.mcgaha@uhn.ca.
