TIGIT and PD-1 impair tumor antigen–specific CD8+ T cells in melanoma patients

Chauvin, Joë-Marc; Pagliano, Ornella; Fourcade, Julien; Sun, Zhaojun; Wang, Hong; Sander, Cindy; Kirkwood, John M.; Chen, Tseng-hui Timothy; Maurer, Mark; Korman, Alan J.; Zarour, Hassane M.

doi:10.1172/jci80445

Cited by 612 publications

(651 citation statements)

References 46 publications

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“…Both activated and exhausted T cells express PD-1, with ex-hausted T cells expressing higher and more persistent levels of PD-1 than activated T cells do (68,71,72). Therefore, instead of relying only on the level of expression of PD-1, in the present study, we also determined coexpression of TIM-3 and 2B4 markers of exhaustion on CD8 ϩ T cells, as well as of two newly reported markers of exhaustion, TIGIT and VISTA (36)(37)(38)73). PD-1, TIM-3, 2B4, TGIT, and VISTA were all coexpressed at various levels on CD8 ϩ T cells from TG of CXCL10 Ϫ/Ϫ deficient mice compared to CD8 ϩ T cells from TG of age-and sex-matched WT B6 mice.…”

Section: Discussionmentioning

confidence: 94%

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

Srivastava

Khan

Chilukuri

et al. 2017

J Virol

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Herpes simplex virus 1 (HSV-1) establishes latency within the sensory neurons of the trigeminal ganglia (TG). HSV-specific memory CD8 ϩ T cells play a critical role in preventing HSV-1 reactivation from TG and subsequent virus shedding in tears that trigger recurrent corneal herpetic disease. The CXC chemokine ligand 10 (CXCL10)/CXC chemokine receptor 3 (CXCR3) chemokine pathway promotes T cell immunity to many viral pathogens, but its importance in CD8 ϩ T cell immunity to recurrent herpes has been poorly elucidated. In this study, we determined how the CXCL10/CXCR3 pathway affects TG-and cornea-resident CD8 ϩ T cell responses to recurrent ocular herpesvirus infection and disease using a well-established murine model in which HSV-1 reactivation was induced from latently infected TG by UV-B light. Following UV-B-induced HSV-1 reactivation, a significant increase in both the number and function of HSV-specific CXCR3 ϩ CD8 ϩ T cells was detected in TG and corneas of protected C57BL/6 (B6) mice, but not in TG and corneas of nonprotected CXCL10 Ϫ/Ϫ or CXCR3 Ϫ/Ϫ deficient mice. This increase was associated with a significant reduction in both virus shedding and recurrent corneal herpetic disease. Furthermore, delivery of exogenous CXCL10 chemokine in TG of CXCL10 Ϫ/Ϫ mice, using the neurotropic adeno-associated virus type 8 (AAV8) vector, boosted the number and function of effector memory CD8 ϩ T cells (T EM ) and tissue-resident memory CD8 ϩ T cells (T RM ), but not of central memory CD8 ϩ T cells (T CM ), locally within TG, and improved protection against recurrent herpesvirus infection and disease in CXCL10 Ϫ/Ϫ deficient mice. These findings demonstrate that the CXCL10/CXCR3 chemokine pathway is critical in shaping CD8 ϩ T cell immunity, locally within latently infected tissues, which protects against recurrent herpesvirus infection and disease.IMPORTANCE We determined how the CXCL10/CXCR3 pathway affects CD8 ϩ T cell responses to recurrent ocular herpesvirus infection and disease. Using a wellestablished murine model, in which HSV-1 reactivation in latently infected trigeminal ganglia was induced by UV-B light, we demonstrated that lack of either CXCL10 chemokine or its CXCR3 receptor compromised the mobilization of functional CD8 ϩ T EM and CD8 ϩ T RM cells within latently infected trigeminal ganglia following virus reactivation. This lack of T cell mobilization was associated with an increase in recurrent ocular herpesvirus infection and disease. Inversely, augmenting the amount of

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Section: Discussionmentioning

confidence: 94%

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

Srivastava

Khan

Chilukuri

et al. 2017

J Virol

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“…Likewise, TIGIT expression on TILs has been shown to be upregulated in other solid cancers such as melanoma, colon cancer, and NSCLC in both mice and humans. 19-21 Moreover, it has been suggested that TIGIT expression may indicate dysfunction of CD8 + TILs and reduced effector function. 19 , 20 , 22 These results support the notion of using anti-TIGIT antibody in cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

“…17 , 18 Elevated TIGIT expression on CD8 + T cells and Tregs has been shown to confer an overall suppressive phenotype, correlating with reduced cytokine production and poor survival in multiple cancer models. 19-22 Moreover, this effect was further suggested to be mediated by dendritic cells (DCs), which can regulate the TIGIT pathway via the expression of CD155. 16 In the clinical setting, prior studies have demonstrated an elevated expression of CD155 on human GBM cells and increased TIGIT expression on patient CD8 + tumor-infiltrating lymphocytes (TILs), rendering this pathway as a potential therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

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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“…Dual blockade of 2 immune checkpoints enhance function of tumor infiltrating lymphocytes (TILs) and tumor antigen-specific CD8 þ T cells, thereby, results in significant tumor rejection. 33,34 Lymphocyte activation gene-3 (LAG3) is an immune checkpoint upregulated on activated T cells, T reg , and NK cells. As a homologue to CD4, LAG3 expressed on effector CD4 þ T cells is deemed as a negative modulator tending to have interaction with major histocompatibility complex (MHC) II molecules.…”

Section: Combination Strategiesmentioning

confidence: 99%

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

Marinis

Ardizzoni

Fontanini

et al. 2014

Clinical Lung Cancer

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TIGIT and PD-1 impair tumor antigen–specific CD8+ T cells in melanoma patients

Cited by 612 publications

References 46 publications

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

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

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

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TIGIT and PD-1 impair tumor antigen–specific CD8+ T cells in melanoma patients

Cited by 612 publications

References 46 publications

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 + T EM and CD8 + T RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 + T EM and CD8 + T RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

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

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

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CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease