Abstract
Cancer immunotherapy has made remarkable clinical advances in recent years. Antibodies targeting the immune checkpoint receptors PD-1 and CTLA-4 and adoptive cell therapy (ACT) based on ex vivo expanded peripheral CTLs, tumor infiltrating lymphocytes (TILs), gene-engineered TCR- and chimeric antigen receptor (CAR)-T cells have all shown durable clinical efficacies in multiple types of cancers. However, these immunotherapeutic approaches only benefit a small fraction of cancer patients as various immune resistance mechanisms and limitations make their effective use a challenge in the majority of cancer patients. For example, adaptive resistance to therapeutic PD-1 blockade is associated with an upregulation of some additional immune checkpoint receptors. The efficacy of transferred tumor-specific T cells under the current clinical ACT protocol is often limited by their inefficient engraftment, poor persistence, and weak capability to attack tumor cells. Recent studies demonstrate that the complement receptor C3aR and C5aR function as a new class of immune checkpoint receptors. Complement signaling through C3aR and C5aR expressed on effector T lymphocytes prevent the production of the cytokine interleukin-10 (IL-10). Removing C3aR/C5aR-mediated transcriptional suppression of IL-10 expression results in endogenous IL-10 production by antitumor effector T cells, which drives T cell expansion and enhances T cell-mediated antitumor immunity. Importantly, preclinical, and clinical data suggest that a signaling axis consisting of complement/C3aR/C5aR/IL-10 critically regulates T cell mediated antitumor immunity and manipulation of the pathway ex vivo and in vivo is an effective strategy for cancer immunotherapy. Furthermore, a combination of treatment strategies targeting the complement/C3aR/C5aR/IL-10 pathway with other treatment modalities may improve cancer therapeutic efficacy.
Highlights
As a major component of the innate immunity, the complement system directly regulates lymphocyte function [1, 2]
Complement Receptors in Cancer Immunotherapy complement levels are positively correlated with tumor size and poor outcome in different types of cancers, such as neuroblastoma, colorectal, lung, ovarian cancer, chronic lymphocytic leukemia, and carcinomas of the digestive tract [3]
Recent studies suggest that a new mechanism plays an important role in complement signaling-mediated suppression of antitumor immunity: direct inhibition of IL-10 production in CD8+ tumor infiltrating lymphocytes (TILs) in tumor microenvironment (TME) [11, 14]
Summary
As a major component of the innate immunity, the complement system directly regulates lymphocyte function [1, 2]. Recent studies suggest that a new mechanism plays an important role in complement signaling-mediated suppression of antitumor immunity: direct inhibition of IL-10 production in CD8+ tumor infiltrating lymphocytes (TILs) in TME [11, 14]. CD8+ TILs are enhanced in these mice and depletion of T cells through TCRα genetic deletion or antibodies against CD4+ or CD8+ T cells diminishes the enhanced antitumor immunity in the complement signaling deficient models [4, 8,9,10,11,12,13,14,15] These studies suggest that multiple immune suppressive mechanisms are induced by C3aR and C5aR1 signaling (Table 1). To determine the source of complement that mediates immune suppression on CD8+ TILs,
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