Requirement of Treg-intrinsic CTLA4/PKCη signaling pathway for suppressing tumor immunity
Christophe Pedros, Ann J. Canonigo-Balancio, Kok-Fai Kong, Amnon Altman
Christophe Pedros, Ann J. Canonigo-Balancio, Kok-Fai Kong, Amnon Altman
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Research Article Immunology

Requirement of Treg-intrinsic CTLA4/PKCη signaling pathway for suppressing tumor immunity

Abstract

The ability of Tregs to control the development of immune responses is essential for maintaining immune system homeostasis. However, Tregs also inhibit the development of efficient antitumor responses. Here, we explored the characteristics and mechanistic basis of the Treg-intrinsic CTLA4/PKCη signaling pathway that we recently found to be required for contact-dependent Treg-mediated suppression. We show that PKCη is required for the Treg-mediated suppression of tumor immunity in vivo. The presence of PKCη-deficient (Prkch–/–) Tregs in the tumor microenvironment was associated with a significantly increased expression of the costimulatory molecule CD86 on intratumoral CD103+ DCs, enhanced priming of antigen-specific CD8+ T cells, and greater levels of effector cytokines produced by these cells. Similar to mouse Tregs, the GIT/PAK/PIX complex also operated downstream of CTLA4 and PKCη in human Tregs, and GIT2 knockdown in Tregs promoted antitumor immunity. Collectively, our data suggest that targeting the CTLA4/PKCη/GIT/PAK/PIX signaling pathway in Tregs could represent a novel immunotherapeutic strategy to alleviate the negative impact of Tregs on antitumor immune responses.

Authors

Christophe Pedros, Ann J. Canonigo-Balancio, Kok-Fai Kong, Amnon Altman

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Figure 2

The presence of Prkch–/– Tregs reduces tumor growth and increases intratumoral Teff cell accumulation.

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The presence of Prkch–/– Tregs reduces tumor growth and increases intrat...
Rag1−/− mice received CD25-depleted C57BL/6 spleen cells as a source of Teff cells either alone (no Tregs, gray) or together with CD4+GFP+ Tregs from WT (black) or Prkch−/− (white) FIG mice. B16-F10 melanoma cells (0.5 × 106) were inoculated i.d. 1 day later. (A) Tumor sizes were measured 3 times a week to calculate tumor area (mm2), and cumulative data of 3–4 experiments are shown (mean ± SEM). no Tregs, n = 16; + WT Tregs, n = 14; + Prkch−/− Tregs, n = 16. (B–E) Numbers of tumor-infiltrating CD8+ Teff (B), CD4+ Teff (C), and GFP+ Tregs (D) per mg of tumor and CD8/Treg ratios (E) were analyzed in B16-F10 tumors on day 14. Cumulative data of 3 experiments are shown (mean ± SEM). no Tregs, n = 7; + WT Tregs, n = 10; + Prkch−/− Tregs, n = 9. Statistical significance of differences between groups was determined by repeated-measures 2-way ANOVA (A) or 1-way ANOVA (B–E) followed by Tukey’s multiple comparisons test. ns, P > 0.05; *P ≤ 0.05; **P ≤ 0.01; ****P ≤ 0.0001. Statistical significance levels in A are shown against the no Tregs group.