C3aR Signaling Inhibits NK-cell Infiltration into the Tumor Microenvironment in Mouse Models

Many solid tumors have low levels of cytotoxic CD56(dim) natural killer (NK) cells, suggesting that CD56(dim) NK-cell exclusion from the tumor microenvironment (TME) contributes to the decreased response rate of immunotherapy. Complement component 3a (C3a) is known for its tumor-promoting and immunosuppressive roles in solid tumors. Previous reports have implicated the involve-ment of the C3a receptor (C3aR) in immune cell trafficking into the TME. C3aR is predominantly expressed on the surface of activated cytotoxic NK cells, but a specific role for C3aR in NK-cell biology has not been investigated. Because solid tumors generate elevated C3a and have decreased NK-cell infiltration, we hypothesized that C3aR might play a role in cytotoxic NK-cell recruitment into the TME. Our results indicate that blocking C3aR signaling in NK cells increased NK-cell infiltration into the TME in mouse models and led to tumor regression. Because the critical lymphocyte trafficking integrin LFA-1 orchestrates the migration of activated NK cells, we wanted to gain insight into the interaction between C3aR signaling and LFA-1. Our results demonstrated that direct interaction between C3aR and LFA-1, which led to a high-affinity LFA-1 conformation, decr-eased NK-cell infiltration into the TME. We propose that approaches to enhance cytotoxic NK-cell infiltration into the TME, through either disrupting C3a and C3aR interaction or inhibiting the formation of high-affinity LFA-1, represent a new strategy to improve the efficiency of immunotherapy for cancer treatment.

Automated summary

Many solid tumors have low levels of cytotoxic CD56(dim) natural killer (NK) cells, which is thought to contribute to the decreased response rate of immunotherapy. Complement component 3a (C3a) plays a role in immune cell trafficking into the tumor microenvironment (TME). Blocking C3a receptor (C3aR) signaling increases NK cell infiltration into the TME. Direct interaction between C3aR and the lymphocyte trafficking integrin LFA-1 decreases NK cell infiltration into the TME.