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.