Distinct immune microenvironments stratify triple-negative breast cancer and predict outcome
Tina Gruosso1,2,Mathieu Gigoux1*, Nicholas Bertos1*, Venkata Satya Kumar Manem3,4*, Dongmei Zuo1,Sadiq Mehdi Ismail Saleh1,5,6, Hong Zhao1, Margarita Souleimanova1, Radia Marie Johnson1,Anne Monette7, Valentina Muñoz Ramos1,Michael Trevor Hallett5,6,8, John Stagg7, Réjean Lapointe7, Atilla Omeroglu9,Sarkis Meterissian2,10, Laurence Buisseret11, Gert Van den Eyden12, Roberto Salgado11,12, Marie-Christine Guiot9,13,Benjamin Haibe-Kains3,4,14,15, Morag Park1,2,5. 1Goodman Cancer Research Centre, 2Department of Oncology, McGill University, Montreal, Canada, 3 Princess Margaret Cancer Centre, 4Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada, 5Department of Biochemistry, 6Centre for Bioinformatics, McGill University, Montreal, Canada, 7Centre de Recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montréal, Canada, 8School of Computer Science, McGill University, Montreal Canada, 9Department of Pathology,10Surgery, McGill University Health Centre, Montreal, Canada,11Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium, 12Departments of Pathology and Cytology, GZA Hospitals, Wilrijk, Belgium, 13Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada, 14Department of Computer Science, University of Toronto, Toronto, Ontario, Canada, 15Ontario Institute of Cancer Research, Toronto, Ontario, Canada.
Triple negative breast cancer (TNBC) are especially difficult to treat effectively. While only 20-30% of TNBC patients respond to chemotherapy in the neoadjuvant setting, overall outcome remains poor for non-responding patients. Engaging the immune system promises optimal personalized cancer therapy as mounting evidence suggests that immune-checkpoint inhibitor immunotherapies may become a therapeutic option for TNBC patients. The presence of CD8+ T cells, a crucial component of the cytotoxic arm of the adaptive immune response, is associated with good clinical outcome in TNBC patients. Specifically, it is the efficient CD8+ T cell invasion and infiltration in the tumor that is associated with good outcome. On the other hand, some tumors accumulate CD8+ T cells in the tumor-associated stroma with poor infiltration in the tumor epithelium. These patients show poor outcome. As CD8+ T cell infiltration in the tumor is a crucial step to mount an efficient anti-tumor response, we thus wondered how the tumor microenvironment affects CD8+ T cell invasion into the tumor epithelial compartment of the TNBC tumors. To identify potential stroma-dependent mechanisms that potentiate or inhibit CD8+ T cells invasion into the tumor epithelium, we performed gene expression profiling of laser-capture microdissected tumor-associated stroma (as well as matched epithelium and bulk tumor) from 38 TNBC chemotherapy-naive primary cases. Here we identify several pathways and phenotypes that may explain heterogeneity of the CD8+ T cell distribution. These newly identified distinct immune microenvironments of TNBC have implications for patient stratification for immunotherapies.
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