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M1hot tumour associated macrophages are positively associated with tissue-resident memory T cell responses and survival outcomes in human lung cancer (single cells).

ABSTRACT: Tumour-associated macrophages (TAMs) are classified as M1 (“anti-tumour”) and M2 (“pro-tumour”), but their balance has not yet been accurately established in human cancer tissue. Here, we present bulk and single-cell transcriptomic data from human TAMs isolated from lung cancer compared with autologous non-tumour involved lung tissue macrophages (N-TAM). TAMs have a profoundly different transcriptomic profile from N-TAMs and displayed a broad M2 pro-tumour signature that was homogeneous across all the lung cancer patients studied. However, in some tumours, we found TAM populations that simultaneously displayed strong M1 gene expression pattern. These M1hot TAMs appeared to contribute to effective anti-tumour immunity via expression of T cell chemo-attractants (CXCL9, 10 and 11). We found that M1hot TAMs expressed low levels of FABP3, 4 and 5, take up less fatty acids and showed “metabolic generosity” to tissue resident memory T cells (TRM) by allowing them access to this essential nutrient resource that is required for their maintenance. Importantly, tumours harbouring M1hot TAMs were highly enriched for TRM cells and were also associated with improved overall survival outcomes. Our findings suggest that immunotherapeutic approaches aimed at inducing the expression of M1hot program in TAMs rather than generically eliminating all TAMs are likely to be beneficial.

ORGANISM(S): Homo sapiens

PROVIDER: GSE116947 | GEO | 2020/07/29

REPOSITORIES: GEO

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Project description:Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME) which can either promote tumor progression (M2) or induce antitumor immunity (M1). The hypothesis of our study is that the expression of FOLR2 is associated with an M2-like macrophage profile. The main goal of this study is to compare the transcriptomic profile of FOLR2 positive and FOLR2 negative TAMs obtained from the ascites of C57BL/6 mice bearing ovarian ID8 intraperitoneal tumors. Abstract: The immunosuppressive tumor microenvironment (TME) represents a major barrier for effective immunotherapy. Tumor-associated macrophages (TAMs) are highly heterogeneous and plastic cell components of the TME which can either promote tumor progression (M2-like) or boost antitumor immunity (M1-like). Selective targeting of the pro-tumorigenic subset of TAMs represents an attractive therapeutic strategy. Here, we demonstrate that a subset of TAMs that expressing folate receptor β (FRβ) possess an immunosuppressive, tumor-promoting M2-like profile, while FRβ negative TAMs feature pro-inflammatory M1 macrophage properties. In syngeneic tumor mouse models, the administration of FRβ-targeted chimeric antigen receptor (CAR) T-cells mediated elimination of FRβ+ TAMs in the TME, which resulted in an enrichment of pro-inflammatory monocytes, an influx of endogenous tumor-specific CD8+ T-cells, delayed tumor progression, and prolonged survival. Preconditioning of the TME with FRβ-specific CAR T-cells also improved the effectiveness of tumor-directed anti-mesothelin CAR T-cells, while simultaneous co-administration of both CAR products did not. Thus, CAR T-cell-mediated depletion of immunosuppressive M2-like TAMs incites a pro-inflammatory TME that broadens endogenous antitumor immunity and limits tumor progression, highlighting the pro-tumor role of FRβ+ TAMs in the TME and the therapeutic implications of TAM-depleting agents as preparative adjuncts to conventional immunotherapies that directly target tumor antigens.

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M1hot tumour associated macrophages are positively associated with tissue-resident memory T cell responses and survival outcomes in human lung cancer (single cells).

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