Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms

Abstract

Cancer-induced immune responses affect tumor progression and therapeutic response. In multiple murine models and clinical datasets, we identified large variations of neutrophils and macrophages, which define “immune subtypes” of triple negative breast cancer (TNBC) including neutrophil-enriched (NES) and macrophage-enriched subtypes (MES). Different tumor-intrinsic pathways and mutual regulation between macrophages/monocytes and neutrophils contribute to the development of dichotomous myeloid compartment. MES contains predominantly macrophages that are CCR2-dependent and exhibit variable responses to immune checkpoint blockade (ICB). NES exhibits systemic and local accumulation of immunosuppressive neutrophils (or granulocytic myeloid-derived suppressor cells (gMDSCs), is resistant to ICB, and contains a minority of macrophages that appear to be unaffected by CCR2 knockout. A MES-to-NES conversion mediated acquired ICB resistance of initially sensitive MES models. Our results demonstrate diverse myeloid cell frequencies, functionality, and potential roles in immunotherapies, and highlight the need to better understand the inter-patient heterogeneity of the myeloid compartment.

CD163+ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

“…In agreement with our present work, these emerging studies suggest that TAMs may adapt to a variety of tumor microenvironmental clues during tumor development, by acquiring a large spectrum of states. 32 Importantly, recent studies have shown that the use of immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 can modify the myeloid high-dimensional landscape in mouse models, 33,34 providing new insights into its mechanisms of action and its clinical applications.…”

Development and validation of a stromal immune phenotype classifier for predicting immune activity and prognosis in triple‐negative breast cancer

“…The microenvironment of breast cancer has long been recognized to be immunosuppressive, and immunotherapy may not work effectively 28 . Different prediction models have been developed for TNBC clinical outcomes and treatment sensitivity, especially regarding the tumor microenvironment and immune features 15,29 . In addition, intertumor and intratumoral heterogeneity predict not only clinical outcomes but also treatment sensitivity 30 .…”

The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth in combination with adoptive immunotherapy in a mouse model of breast cancer

“…Kim et al recently demonstrated across several murine models of triple negative breast cancer (TNBC) and in patient samples of TNBC that tumor infiltrating neutrophilic myeloid cells (TINs) were immunosuppressive and contribute to poor prognostic outcomes in patients [13]. In contrast, tumor infiltrating macrophages or monocytic myeloid cells (TIMs) were associated with increased responsiveness to checkpoint inhibitors in the murine models and better prognosis in humans [13]. Using guadecitabine treatment, Gr1 + cells are depleted, which include both MDSCs and neutrophils, but beneficial F4/80 + TIMs are not affected (Supplemental Fig.…”

“…MDSCs have been found in the spleen, blood, liver, and tumor of tumor-bearing animals. These suppressive cells have been found to accumulate in various types of murine tumor models and human cancer, from murine hepatic carcinoma models [12], breast cancer models [13], to human ovarian cancer [14], and many more.…”