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Resveratrol exerts antitumor effects by downregulating CD8⁺CD122⁺ Tregs in murine hepatocellular carcinoma.

ABSTRACT: CD4⁺Foxp3⁺ regulatory T cells (Tregs) in the tumor microenvironment restrain antitumor immunity, resulting in tumor aggression and poor survival in hepatocellular carcinoma (HCC). CD8⁺CD122⁺ Tregs have been previously shown to be more potent in immunosuppression than are CD4⁺Foxp3⁺ Tregs. Previous studies have demonstrated that resveratrol exerts its anti-cancer effects by downregulating CD4⁺Foxp3⁺ and M2-like macrophages, two key immunoregulatory cells that maintain the immunosuppressive tumor microenvironment. In this study, we found that resveratrol inhibited the tumor growth in a subcutaneous Hepa1-6 HCC model and decreased the frequency of CD8⁺CD122⁺ Tregs in the tumor as well as lymph nodes and spleen of the tumor-bearing mice. It also increased the percentage of IFN-γ-expressing CD8⁺ T cells in the tumor and peripheral lymphoid organs. The antitumor effects of resveratrol were partially reversed by the adoptive transfer of exogenous CD8⁺CD122⁺ Tregs into the tumor-bearing mice. Meanwhile, resveratrol treatment downregulated immunosuppressive cytokines, including TGF-β1 and interleukin-10, in the tumor while elevating antitumor cytokines, TNF-α and IFN-γ. It also inhibited the activation of STAT3 signaling in the tumor. As expected, resveratrol reduced the percentage of M2-like macrophages in the mice. Importantly, resveratrol suppressed orthotopic H22 tumor growth and decreased the frequency of CD8⁺CD122⁺ Tregs and M2-like macrophages in the tumor-bearing mice. Furthermore, our studies showed that resveratrol, at non-cytotoxic concentrations, inhibited CD8⁺CD122⁺ Treg differentiation from CD8⁺CD122^- T cells in vitro. Thus, our studies unveiled a new immune mechanism underlying the immunosuppressive tumor microenvironment and demonstrated that resveratrol could help reverse it by diminishing CD8⁺CD122⁺ Tregs.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC7588216 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTumor cell death caused by radiation therapy (RT) triggers antitumor immunity in part because dying cells release adjuvant factors that amplify and sustain dendritic cell and T cell responses. We previously demonstrated that bempegaldesleukin (BEMPEG: NKTR-214, an immunostimulatory IL-2 cytokine prodrug) significantly enhanced the antitumor efficacy of RT through a T cell-dependent mechanism. Because RT can induce either immunogenic or tolerogenic cell death, depending on various factors (radiation dose, cell cycle phase), we hypothesized that providing a specific immunogenic adjuvant, like intratumoral therapy with a novel toll-like receptor (TLR) 7/8 agonist, NKTR-262, would improve systemic tumor-specific responses through the activation of local innate immunity. Therefore, we evaluated whether intratumoral NKTR-262 combined with systemic BEMPEG treatment would elicit improved tumor-specific immunity and survival compared with RT combined with BEMPEG.MethodsTumor-bearing mice (CT26; EMT6) received BEMPEG (0.8 mg/kg; intravenously), RT (12 Gy × 1), and/or intratumoral NKTR-262 (0.5 mg/kg). Flow cytometry was used to evaluate CD4+ and CD8+ T cell responses in the blood and tumor 7 days post-treatment. The contribution of specific immune subsets was determined by depletion of CD4+, CD8+, or NK cells. CD8+ T cell cytolytic activity was determined by an in vitro CTL assay. Data are representative of 1-2 independent experiments (n=5-14/group) and statistical significance was determined by 1-way analysis of variance (ANOVA) or repeated measures ANOVA (p value cut-off of 0.05).ResultsBEMPEG+NKTR-262 significantly improved survival compared with BEMPEG+RT in a CD8+ T cell-dependent manner. Response to BEMPEG+NKTR-262 was characterized by a significant expansion of activated CD8+ T cells (GzmA+; Ki-67+; ICOS+; PD-1+) in the blood, which correlated with reduced tumor size (p<0.05). In the tumor, BEMPEG+NKTR-262 induced higher frequencies of GzmA+ CD8+ T cells exhibiting reduced expression of suppressive molecules (PD-1+), compared with BEMPEG+RT (p<0.05). Further, BEMPEG+NKTR-262 treatment induced greater tumor-specific CD8+ T cell cytolytic function than BEMPEG+RT.ConclusionsBEMPEG+NKTR-262 therapy elicited more robust expansion of activated CD8+ T cells compared with BEMPEG+RT, suggesting that intratumoral TLR stimulation provides superior antigen presentation and costimulatory activity compared with RT. A clinical trial of BEMPEG+NKTR-262 for patients with metastatic solid tumors is in progress (NCT03435640).

Project description:Due to vigorous alloimmunity, an allograft is usually rejected without any conventional immunosuppressive treatment. However, continuous global immunosuppression may cause severe side effects, including tumors and infections. Mounting evidence has shown that cyclosporine (CsA), a common immunosuppressant used in clinic, impedes allograft tolerance by dampening regulatory T cells (Tregs), although it inhibits allograft rejection at the same time. Therefore, it is necessary to seek an alternative immunosuppressive drug that spares Tregs with high efficiency in suppression but low toxicity. In this study, we investigated the capacity of emodin, an anthraquinone molecule originally extracted from certain natural plants, to prolong transplant survival in a mouse model and explored the cellular and molecular mechanisms underlying its action. We found that emodin significantly extended skin allograft survival and hindered CD3+ T cell infiltration in the allograft, accompanied by an increase in CD4+Foxp3+ and CD8+CD122+ Treg frequencies and numbers but a reduction in effector CD8+CD44highCD62Llow T cells in recipient mice. Emodin also inhibited effector CD8+ T cells proliferation in vivo. However, CD4+CD25+, but not CD8+CD122+, Tregs derived from emodin-treated recipients were more potent in suppression of allograft rejection than those isolated from control recipients, suggesting that emodin also enhances the suppressive function of CD4+CD25+ Tregs. Interestingly, depleting CD25+ Tregs largely reversed skin allograft survival prolonged by emodin while depleting CD122+ Tregs only partially abrogated the same allograft survival. Furthermore, we found that emodin hindered dendritic cell (DC) maturation and reduced alloantibody production posttransplantation. Finally, we demonstrated that emodin inhibited in vitro proliferation of T cells and blocked their mTOR signaling as well. Therefore, emodin may be a novel mTOR inhibitor that suppresses alloimmunity by inducing both CD4+FoxP3+ and CD8+CD122+ Tregs, suppressing alloantibody production, and hindering DC maturation. Thus, emodin is a newly emerging immunosuppressant and could be utilized in clinical transplantation in the future.

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Resveratrol exerts antitumor effects by downregulating CD8⁺CD122⁺ Tregs in murine hepatocellular carcinoma.

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Resveratrol exerts antitumor effects by downregulating CD8+CD122+ Tregs in murine hepatocellular carcinoma.

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Resveratrol exerts antitumor effects by downregulating CD8⁺CD122⁺ Tregs in murine hepatocellular carcinoma.