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JCI Insight. 2017 May 4;2(9). pii: 90201. doi: 10.1172/jci.insight.90201. eCollection 2017 May 4.

C3d regulates immune checkpoint blockade and enhances antitumor immunity.

Author information

1
Department of Microbiology and Immunology.
2
Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
3
Department of Dermatology, UCLA, Los Angeles, California, USA.
4
Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
5
Center for Vaccines and Immunology, Department of Infectious Diseases, The University of Georgia, Athens, Georgia, USA.
6
Department of Pediatrics, Graduate Program in Immunology, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

Despite expression of immunogenic polypeptides, tumors escape immune surveillance by engaging T cell checkpoint regulators and expanding Tregs, among other mechanisms. What orchestrates these controls is unknown. We report that free C3d, a fragment of the third component of complement, inside tumor cells - or associated with irradiated tumor cells and unattached to antigen - recruits, accelerates, and amplifies antitumor T cell responses, allowing immunity to reverse or even to prevent tumor growth. C3d enhances antitumor immunity independently of B cells, NK cells, or antibodies, but it does so by increasing tumor infiltrating CD8+ lymphocytes, by depleting Tregs, and by suppressing expression of programmed cell death protein 1 (PD-1) by T cells. These properties of C3d appear specific for the tumor and dependent on complement receptor 2, and they incur no obvious systemic toxicity. The heretofore unrecognized properties of free C3d suggest that protein might determine the effectiveness of immune surveillance and that increasing availability of the protein might prove advantageous in the treatment or prevention of cancer and premalignant conditions.

KEYWORDS:

Immunology

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