In contrast to its inhibitory effects on many cells, IL10 activates CD8⁺ tumor-infiltrating lymphocytes (TIL) and enhances their antitumor activity. However, CD8⁺ TILs do not routinely express IL10, as autocrine complement C3 inhibits IL10 production through complement receptors C3aR and C5aR. CD8⁺ TILs from C3-deficient mice, however, express IL10 and exhibit enhanced effector function. C3-deficient mice are resistant to tumor development in a T-cell– and IL10-dependent manner; human TILs expanded with IL2 plus IL10 increase the killing of primary tumors in vitro compared with IL2-treated TILs. Complement-mediated inhibition of antitumor immunity is independent of the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) immune checkpoint pathway. Our findings suggest that complement receptors C3aR and C5aR expressed on CD8⁺ TILs represent a novel class of immune checkpoints that could be targeted for tumor immunotherapy. Moreover, incorporation of IL10 in the expansion of TILs and in gene-engineered T cells for adoptive cell therapy enhances their antitumor efficacy.

Significance: Our data suggest novel strategies to enhance immunotherapies: a combined blockade of complement signaling by antagonists to C3aR, C5aR, and anti–PD-1 to enhance anti–PD-1 efficacy; a targeted IL10 delivery to CD8⁺ TILs using anti–PD-1–IL10 or anti-CTLA4–IL10 fusion proteins; and the addition of IL10 in TIL expansion for adoptive cellular therapy. Cancer Discov; 6(9); 1022–35. ©2016 AACR.

See related commentary by Peng et al., p. 953.

This article is highlighted in the In This Issue feature, p. 932