C1q+ tumor-associated macrophages contribute to immunosuppression through fatty acid metabolic reprogramming in malignant pleural effusion

Abstract

Background: Although immune checkpoint blockade (ICB) therapy has shown remarkable benefits in cancers, a subset of patients with cancer exhibits unresponsiveness or develop acquired resistance due to the existence of abundant immunosuppressive cells. Tumor-associated macrophages (TAMs), as the dominant immunosuppressive population, impede the antitumor immune response; however, the underlying mechanisms have not been fully elucidated yet.

Methods: Single-cell RNA sequencing analysis was performed to portray macrophage landscape and revealed the underlying mechanism of component 1q (C1q)⁺ TAMs. Malignant pleural effusion (MPE) of human and mouse was used to explore the phenotypes and functions of C1q⁺ TAMs.

Results: C1q⁺ TAMs highly expressed multiple inhibitory molecules and their high infiltration was significantly correlated with poor prognosis. C1q⁺ TAMs promote MPE immunosuppression through impairing the antitumor effects of CD8⁺ T cells. Mechanistically, C1q⁺ TAMs enhance fatty acid binding protein 5 (FABP5)-mediated fatty acid metabolism, which activate transcription factor peroxisome proliferator-activated receptor-gamma, increasing the gene expression of inhibitory molecules. A high-fat diet increases the expression of inhibitory molecules in C1q⁺ TAMs and the immunosuppression of MPE microenvironment, whereas a low-fat diet ameliorates these effects. Moreover, FABP5 inhibition represses the expression of inhibitory molecules in TAMs and tumor progression, while enhancing the efficacy of ICB therapy in MPE and lung cancer.

Conclusions: C1q⁺ TAMs impede antitumor effects of CD8⁺ T cells promoting MPE immunosuppression. Targeting C1q⁺ TAMs effectively alleviates the immunosuppression and enhances the efficacy of ICB therapy. C1q⁺ TAMs subset has great potential to be a therapeutic target for cancer immunotherapy.

Keywords: immunomodulation; immunotherapy; lymphocytes, tumor-infiltrating; macrophages; tumor microenvironment.