Corrigendum: Effective Anti-tumor Response by TIGIT Blockade Associated With FcγR Engagement and Myeloid Cell Activation.

[This corrects the article DOI: 10.3389/fimmu.2020.573405.].

Effective Anti-tumor Response by TIGIT Blockade Associated With FcγR Engagement and Myeloid Cell Activation.

The molecule "T cell immunoreceptor with immunoglobulin and ITIM domain," or TIGIT, has recently received much attention as a promising target in the treatment of various malignancies. In spite of the quick progression of anti-TIGIT antibodies into clinical testing both as monotherapy and in combination with programmed cell death-1 (PD-1)-directed immune checkpoint blockade, the molecular mechanism behind the observed therapeutic benefits remains poorly understood. Here we demonstrate, using mouse tumor models, that TIGIT blocking antibodies with functional Fc binding potential induce effective anti-tumor response. Our observations reveal that the anti-TIGIT therapeutic effect is not achieved by depletion of intratumoral regulatory T cells (Treg) or any cell population expressing TIGIT, but instead is mediated by possible "reverse activating signals" through FcγRs on myeloid cells, inducing expression of various mediators such as cytokines and chemokines. Furthermore, we discovered an induction of a robust and persistent granzyme B and perforin response, distinct from a predominantly interferon-γ (IFN-γ)-driven anti-PD-1 blockade. Our observations, for the first time, provide the basis for a mechanistic hypothesis involving the requirement of a functional Fc domain of anti-TIGIT monoclonal antibodies, of which various isotypes are currently under intense clinical investigation.

The CD200 receptor is a novel and potent regulator of murine and human mast cell function.

CD200R is a member of the Ig supergene family that is primarily expressed on myeloid cells. Recent in vivo studies have suggested that CD200R is an inhibitory receptor capable of regulating the activation threshold of inflammatory immune responses. Here we provide definitive evidence that CD200R is expressed on mouse and human mast cells and that engagement of CD200R by agonist Abs or ligand results in a potent inhibition of mast cell degranulation and cytokine secretion responses. CD200R-mediated inhibition of FcepsilonRI activation was observed both in vitro and in vivo and did not require the coligation of CD200R to FcepsilonRI. Unlike the majority of myeloid inhibitory receptors, CD200R does not contain a phosphatase recruiting inhibitory motif (ITIM); therefore, we conclude that CD200R represents a novel and potent inhibitory receptor that can be targeted in vivo to regulate mast cell-dependent pathologies.

Characterization of the CD200 receptor family in mice and humans and their interactions with CD200.

CD200 (OX2) is a broadly distributed cell surface glycoprotein that interacts with a structurally related receptor (CD200R) expressed on rodent myeloid cells and is involved in regulation of macrophage function. We report the first characterization of human CD200R (hCD200R) and define its binding characteristics to hCD200. We also report the identification of a closely related gene to hCD200R, designated hCD200RLa, and four mouse CD200R-related genes (termed mCD200RLa-d). CD200, CD200R, and CD200R-related genes were closely linked in humans and mice, suggesting that these genes arose by gene duplication. The distributions of the receptor genes were determined by quantitative RT-PCR, and protein expression was confirmed by a set of novel mAbs. The distribution of mouse and human CD200R was similar, with strongest labeling of macrophages and neutrophils, but also other leukocytes, including monocytes, mast cells, and T lymphocytes. Two mCD200 receptor-like family members, designated mCD200RLa and mCD200RLb, were shown to pair with the activatory adaptor protein, DAP12, suggesting that these receptors would transmit strong activating signals in contrast to the apparent inhibitory signal delivered by triggering the CD200R. Despite substantial sequence homology with mCD200R, mCD200RLa and mCD200RLb did not bind mCD200, and presently have unknown ligands. The CD200 receptor gene family resembles the signal regulatory proteins and killer Ig-related receptors in having receptor family members with potential activatory and inhibitory functions that may play important roles in immune regulation and balance. Because manipulation of the CD200-CD200R interaction affects the outcome of rodent disease models, targeting of this pathway may have therapeutic utility.