Blockade of C5a receptor unleashes tumor-associated macrophage antitumor response and enhances CXCL9-dependent CD8+ T cell activity

• Published in: Molecular therapy Vol. 32; no. 2; pp. 469 - 489
• Main Authors: Luan, Xiaojin, Lei, Ting, Fang, Jie, Liu, Xue, Fu, Huijia, Li, Yiran, Chu, Wei, Jiang, Peng, Tong, Chao, Qi, Hongbo, Fu, Yong
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 07.02.2024
• Subjects: chemokine C-X-C motif ligand 9; complement C5a receptor; immunotherapy; ovarian cancer; T cell dysfunction; tumor-associated macrophages; complement C5a receptor; chemokine C-X-C motif ligand 9; ovarian cancer; T cell dysfunction; immunotherapy; tumor-associated macrophages
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2023.12.010

Macrophages play a crucial role in shaping the immune state within the tumor microenvironment (TME) and are often influenced by tumors to hinder antitumor immunity. However, the underlying mechanisms are still elusive. Here, we observed abnormal expression of complement 5a receptor (C5aR) in human ovarian cancer (OC), and identified high levels of C5aR expression on tumor-associated macrophages (TAMs), which led to the polarization of TAMs toward an immunosuppressive phenotype. C5aR knockout or inhibitor treatment restored TAM antitumor response and attenuated tumor progression. Mechanistically, C5aR deficiency reprogrammed macrophages from a protumor state to an antitumor state, associating with the upregulation of immune response and stimulation pathways, which in turn resulted in the enhanced antitumor response of cytotoxic T cells in a manner dependent on chemokine (C-X-C motif) ligand 9 (CXCL9). The pharmacological inhibition of C5aR also improved the efficacy of immune checkpoint blockade therapy. In patients, C5aR expression associated with CXCL9 production and infiltration of CD8+ T cells, and a high C5aR level predicted poor clinical outcomes and worse benefits from anti-PD-1 therapy. Thus, our study sheds light on the mechanisms underlying the modulation of TAM antitumor immune response by the C5a-C5aR axis and highlights the potential of targeting C5aR for clinical applications. [Display omitted] Fu and colleagues revealed that C5aR is a molecular switch controlling TAM antitumor activity, investigated the mechanisms underlying the modulation of TAM antitumor immune response by the C5a-C5aR axis, and proposed that the C5a-C5aR axis may serve as a potential biomarker for T cell dysfunction and the response to immunotherapy.