Tumor-Infiltrating Regulatory Dendritic Cells Inhibit CD8+ T Cell Function via <scp>l</scp>-Arginine Metabolism

Norian, Lyse A.; Rodríguez, Paulo C.; O'Mara, Leigh A.; Zabaleta, Jovanny; Ochoa, Augusto C.; Cella, Marina; Allen, Paul M.

doi:10.1158/0008-5472.can-08-2826

Cited by 238 publications

(215 citation statements)

References 44 publications

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“…The authors also distinguished this population of DCs from myeloid derived suppressor cells (MDSCs), a distinctive cell population known for its immune suppressive activity in cancer models. 32 In our study, we found that combinatorial therapy correlated with a significantly lower frequency of CD11b + CD11 c + TIDCs. Further gating on MHCII expression revealed a significant reduction in CD11b + CD11 c + MHCII hi TIDCs in all treated groups relative to control.…”

Section: Discussionsupporting

confidence: 52%

“…A prior study has shown that TIDCs with high MHCII expression (CD11b + CD11 c + MHCII hi ) may inhibit CD8 + T cell function in the setting of murine mammary carcinoma. 32 In our study, brains of untreated mice had a significantly greater percentage (10.64% ± 2.23) of tumor-infiltrating CD11b + CD11 c + MHCII hi cells than brains of mice receiving anti-PD-1 antibody alone (1.984% ± 0.48; p = 0.0054), anti-TIGIT antibody alone (4.148% ± 2.04; p = 0.0399), or both checkpoint inhibitors (0.908% ± 0.35; p = 0.0020). No significant difference was observed across the three treatment groups (Fig.…”

Section: Resultsmentioning

confidence: 99%

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TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

et al. 2018

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The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc+ tumors, we found that TIGIT expression was upregulated on CD8+ and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.

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Section: Discussionsupporting

confidence: 52%

Section: Resultsmentioning

confidence: 99%

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

et al. 2018

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“…For instance, murine lung cancer could "educate" cDCs to differentiate into CD11c low CD11b high Ia low regDCs that inhibit T cell response, as was reported by Liu et al using the freshly isolated tumor cells to mimic the tumor microenvironment in DC co-culture studies [13]. Norian [14]. An altered cell fate program characterized by minimal T cell expansion, impaired IFN-γ production, and anergy is resulted from the stimulation of naïve T cells with these regDCs.…”

Section: Introduction: Regulatory Dendritic Cells In Cancermentioning

confidence: 85%

“…Expression of inhibitory molecules on regDCs, like programmed cell death 1 ligand 1 (PD-L1) and PD-L2, is another pathway responsible for regDC-mediated inhibition of anti-tumor immunity. Although these and other mechanisms of immunosuppression induced by regDCs have been reported [14,[30][31][32][33][34], it is still unknown which tumor-derived factors or local microenvironmental stimuli are responsible for polarization of cDCs into regDCs in different model systems and for differential expression of a variety of immunosuppressive molecules in regDCs in different conditions. Interestingly, Kuang et al have recently reported that hyaluronan fragments derived from cancer cells drove human monocytes to become tolerogenic semimature DCs, which triggered rapid down-regulation of CD3-ε and TCR-α/β and subsequent apoptosis in autologous T cells [35].…”

Section: Immunosuppressive and Tolerogenic Activity Of Regulatory Denmentioning

confidence: 99%

“…Additional Tolerogenic Pathways in regDCs: Arginase 1 Several years ago, tumor-infiltrating regulatory DCs were reported to inhibit CD8 + T cell function via L-arginine metabolism [14]. The authors were working on the mechanism by which tumor-associated DCs suppressed T cell proliferation and revealed that tumor-associated DCs incorporated five times more L-arginine than did control DCs.…”

Section: Immunosuppressive and Tolerogenic Activity Of Regulatory Denmentioning

confidence: 99%

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Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

Shurin

2013

Cancer Microenvironment

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Three major functional subsets of dendritic cells (DCs) have been described in the tumor microenvironment in patients with cancer and tumor-bearing animals: (i) conventional DCs with intact antigen-presenting capabilities, (ii) functionally defective DCs with decreased motility and low ability to uptake, process and present antigens or produce cytokines and (iii) regulatory DCs with high capacity to suppress T cell proliferation, induce differentiation of regulatory T cells or support immune tolerance. Phenotypic characteristics of regulatory DCs (regDCs), as well as the mechanisms of T cell inhibition, vary in different experimental conditions and environments, suggesting high level of their plasticity and probably different origin. Although new data demonstrate that regDCs may play an important role at early stages of tumor development, functional differences and clinical significance of emergence of different myeloid regulatory cells (MDSCs, regDCs, M2 macrophages, N2 neutrophils, mast cells) in cancer remain to be determined.

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Suppressive Myeloid Cells Shape the Tumor Immune Microenvironment

Xiong

Wang

2021

Advanced Biology

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Cancer is the outcome of the conflict between the host immune system and cancer cells. The crosstalk between immune cells and tumor cells within the tumor microenvironment (TME) influences tumor progression and metastasis. Many studies have clarified the cellular and molecular events that can induce cancer cells to escape immune surveillance, including those involving tumor‐induced myeloid cell‐mediated immunosuppression. Emerging evidence indicates that tumor‐infiltrating myeloid cells (TIMs) accelerate tumor growth and induce angiogenesis, metastasis, and therapy resistance once converted into potent immunosuppressive cells. Here, how tumor infiltrating myeloid cells participate in tumor immune evasion and the prospects of these cells in cancer immunotherapy are discussed.

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Tumor-Infiltrating Regulatory Dendritic Cells Inhibit CD8+ T Cell Function via l-Arginine Metabolism

Cited by 238 publications

References 44 publications

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

Suppressive Myeloid Cells Shape the Tumor Immune Microenvironment

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