Dr. Sara Lamorte

Conference 2024 Live Talk

Talk Title

Medullary sinus macrophages limit cancer therapy efficacy by an efferocytosis-induced IL-33/ST2 axis in the tumor-draining lymph node

Authors and Affiliations

Sara Lamorte1,2, Luke Neufeld1,2, Rene Quevedo1,2, Xin Zhang1,2, M. Teresa Ciudad1,2, Robbie Jin1,2, Zhe Qi Liu1,2, Nadine Nzirorera1,2, Zaid Kamil Saeed3, Hal Berman1,3, David Munn4,5, Mikael C.I. Karlsson6, Tak W. Mak1,2, David G. Brooks1,2, and Tracy L. McGaha1,2.

1- Princess Margaret Cancer Centre. University Health Network. Toronto, Ontario, Canada.
2- Department of Immunology. University of Toronto. Toronto, Ontario, Canada.
3- Department of Laboratory Medicine and Pathobiology. University of Toronto. Toronto, Ontario, Canada.
4- Department of Pediatrics. Medical College of Georgia. Augusta, Georgia.
5- Georgia Cancer Center. Augusta, Georgia. USA.
6- Department of Microbiology, Tumor and Cell Biology. Karolinska Institute. Stockholm, Sweden.

Abstract

Background

Cell death is a fundamental aspect of tissue homeostasis that can expose potentially immunogenic cell components that must be removed to prevent inflammatory autoimmunity. We have shown immune suppression in response to apoptotic cell phagocytosis (a process called efferocytosis) is dependent on tissue-resident macrophages (M). Indeed, if we disrupt M regulatory responses post-efferocytosis, the same apoptotic cells induce inflammation suggesting M responses to dying cells are a key determinant of tolerance. We predict that resident macrophages lining the lymphatic sinus inside the lymph nodes are responsible for tolerance against tumor apoptotic cells.

Methods

bearing mice were treated with chemotherapy or targeted therapy to induce tumor cell death. Both tumor and the tumor-draining lymph node (TDLN) were analyzed at different time points after treatment. In some experiments, we used a novel mouse model, generated in our laboratory, where Il33 was specifically deleted in a subpopulation of macrophages of TDLN, called medullary sinus M (MSM) (MSM-IL33ko).

Results

Using our mouse melanoma model, we observed that after either chemotherapy or targeted therapy MSM avidly phagocytosed dying tumor cells and acquired a tolerogenic phenotype. RNA sequencing analysis revealed MSM rapidly and exclusively induced expression of the alarmin IL-33 as opposed to other M or dendritic cell populations in the TDLN. Importantly, genetic deletion of Il33 (MSM-IL33ko) or blockade of the IL-33 receptor ST2 with IgG, transformed responses to both chemotherapy or targeted therapy with prolonged, enhanced tumor control and reduced cancer reoccurrence. Functionally, MSM-derived IL-33 triggered accumulation and activation of regulatory T cells in the TDLN which then migrated to the tumor limiting intratumoral CD8+ T cell function.

Conclusions

Our data revealed a previously undescribed tumor cell death-induced mechanism limiting anti-cancer immunity and therapy efficacy.