Dysfunction of HPV16-specific CD8+ T cells derived from oropharyngeal tumors is related to the expression of Tim-3 but not PD-1

Hladíková, Kamila; Partlová, Simona; Koucký, Vladimír; Bouček, J; Fonteneau, Jean-François; Zábrodský, Michal; Tachezy, Ruth; Grega, Marek; Špíšek, Radek; Fialová, Alena

doi:10.1016/j.oraloncology.2018.05.010

Cited by 13 publications

(15 citation statements)

References 31 publications

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“…S8D). These findings are in line with data from other groups identifying the negative impact of TIM-3 expression on tumor-infiltrating CD8 þ T cells in multiple oncological settings (27,(35)(36)(37)(38). Moreover, they suggest that targeting TIM-3 with immune-checkpoint blockers may be a particularly promising approach for the treatment of HGSC.…”

Section: Discussionsupporting

confidence: 89%

TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer

Fučíková

Rakova

Hensler

et al. 2019

Clinical Cancer Research

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Purpose: In multiple oncological settings, expression of the coinhibitory ligand PD-L1 by malignant cells and tumor infiltration by immune cells expressing coinhibitory receptors such as PD-1, CTLA4, LAG-3, or TIM-3 conveys prognostic or predictive information. Conversely, the impact of these features of the tumor microenvironment on disease outcome among high-grade serous carcinoma (HGSC) patients remains controversial. Experimental Design: We harnessed a retrospective cohort of 80 chemotherapy-na€ ve HGSC patients to investigate PD-L1 expression and tumor infiltration by CD8 þ T cells, CD20 þ B cells, DC-LAMP þ dendritic cells as well as by PD-1 þ , CTLA4 þ , LAG-3 þ , and TIM-3 þ cells in relation with prognosis and function orientation of the tumor microenvironment. IHC data were complemented with transcriptomic and functional studies on a second prospective cohort of freshly resected HGSC samples. In silico analysis of publicly available RNA expression data from 308 HGSC samples was used as a confirmatory approach. Results: High levels of PD-L1 and high densities of PD-1 þ cells in the microenvironment of HGSCs were strongly associated with an immune contexture characterized by a robust T H 1 polarization and cytotoxic orientation that enabled superior clinical benefits. Moreover, PD-1 þ TIM-3 þ CD8 þ T cells presented all features of functional exhaustion and correlated with poor disease outcome. However, although PD-L1 levels and tumor infiltration by TIM-3 þ cells improved patient stratification based on the intratumoral abundance of CD8 þ T cells, the amount of PD-1 þ cells failed to do so. Conclusions: Our data indicate that PD-L1 and TIM-3 constitute prognostically relevant biomarkers of active and suppressed immune responses against HGSC, respectively.

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Section: Discussionsupporting

confidence: 89%

TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer

Fučíková

Rakova

Hensler

et al. 2019

Clinical Cancer Research

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“…By analyzing downloaded single cell sequencing data, we identified the underlying function of these hub genes. We found that in the HNSCC population, the hub genes had a stable co-expression, which was related to immune cell infiltration, especially CD8+ T cells, and the infiltrative cells were in a dysfunctional status, which had corresponded with several previous studies [23,24]. HPV + ve.…”

Section: Discussionsupporting

confidence: 83%

“…We found that expression of hub genes has a positive association with T cell dysfunction in tumor. HPV + ve HNSCC population has been found to have a typical T cell infiltration in, especially CD4+ and CD8+ T cells [ 14 – 16 ], and feature a high level of immune cells infiltration but high degrees of immunosuppression [ 23 , 24 , 44 ]. Our result corresponded previous studies.…”

Section: Discussionmentioning

confidence: 99%

HPV infection related immune infiltration gene associated therapeutic strategy and clinical outcome in HNSCC

Zeng

Song

et al. 2020

BMC Cancer

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Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common tumor in human. Research has shown that HPV status HNSCC is a unique prognosis factor, which may due to its immune infiltration landscape. But the underlying mechanism is unclear. Methods: In this study, we used a combination of several bioinformatics tools, including WCGNA, ssGSEA, CIBERSORT, TIDE,etc., to explore significant genes both related to HPV infection status and immune cell infiltration in HNSCC patients. Results: Combined with several bioinformatics algorithms, eight hub genes were identified, including LTB, CD19, CD3D, SKAP1, KLRB1, CCL19, TBC1D10C and ARHGAP4. In HNSCC population, the hub genes had a stable coexpression, which was related to immune cell infiltration, especially CD8+ T cells, and the infiltrative immune cells were in a dysfunctional status. Samples with high hub genes expression presented with better response to immune check point block (ICB) therapy and sensitivity to bleomycin and methotrexate. Conclusions: The eight hub genes we found presented with a stable co-expression in immune cell infiltration of HPV + ve HNSCC population. The co-expression of hub genes related to an immune microenvironment featuring an increase in immune cells but high degree of immune dysfunction status. Patients with high hub gene expression had a better response to ICB treatment, bleomycin and methotrexate. The co-expression of hub genes may be related to immune infiltration status in patients. The concrete molecular mechanism of hub genes function demands further exploration.

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“…Some studies have shown that Tim-3 is co-expressed with PD-1 in exhausted T cells in the context of antimicrobial responses [23,24]. In addition, in mice lacking systemic PD-1 in the context of acute myeloid leukemia (AML), T cells express high levels of Tim-3 [12], supporting the notion that compensatory pathways are upregulated in the absence of PD-1. In this study, to investigate Tim-3 expression on T cells after PD-1 blockade, we divided the mice (in the Anchored GM-CSF vaccine+anti-PD-1 antibody group) into sensitive and resistant groups according to the change in tumor size.…”

Section: Discussionmentioning

confidence: 97%

“…Several studies have demonstrated that PD-1 blockade could upregulate the expression of T cell immunoglobulin and mucin domain protein-3 (Tim-3) in head and neck cancer [10] and lung cancer [11]. In addition, the level of upregulated Tim-3 expression was negatively correlated with the function of CD8 + T cells [12]. The role of Tim-3 in the immune regulation of tumors, including PCa, has been confirmed by many studies [13][14][15][16].…”

Section: Ivyspringmentioning

confidence: 99%

Increased Tim-3 expression on TILs during treatment with the Anchored GM-CSF vaccine and anti-PD-1 antibodies is inversely correlated with response in prostate cancer

Zhang¹,

Chen²,

Li³

et al. 2020

J. Cancer

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Programmed death receptor-1 (PD-1) and T cell immunoglobulin and mucin domain-containing protein-3 (Tim-3) play important roles in tumor immune evasion. PD-1 blockade could produce an effective antitumor effect in many solid tumors except prostate cancer (PCa) because of rare programmed death ligand-1 (PD-L1) expression on PCa cells. Streptavidin (SA)-GM-CSF surface-anchored tumor cell (Anchored GM-CSF) vaccines could increase the number of tumor-infiltrating lymphocytes (TILs) and induce specific antitumor immune responses. The Anchored-GM-CSF vaccine and anti-PD-1 antibodies exerted synergistic effects in mouse models of PCa metastasis. However, the response rate was low due to the presence of other negative regulatory pathways. Tim-3 expression could be upregulated at resistance to combination therapy with anti-PD-1 antibodies and the Anchored GM-CSF vaccine. Sequential administration of anti-PD-1 and anti-Tim-3 antibodies could further improve the efficacy of the Anchored GM-CSF vaccine therapy, and tumor regression was noted in over 60% of animals. This triple therapy improved the specific cytotoxic activity, proliferation and secretion of CD8 + TILs and reduced the production of tumor-promoting cytokines. These findings indicated that this triple therapy could induce a robust antitumor immune response in mouse models of PCa.Key words: programmed death receptor-1, T cell immunoglobulin and mucin domain-containing protein-3, prostate cancer, vaccine, immunotherapy.

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Dysfunction of HPV16-specific CD8+ T cells derived from oropharyngeal tumors is related to the expression of Tim-3 but not PD-1

Cited by 13 publications

References 31 publications

TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer

TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer

HPV infection related immune infiltration gene associated therapeutic strategy and clinical outcome in HNSCC

Increased Tim-3 expression on TILs during treatment with the Anchored GM-CSF vaccine and anti-PD-1 antibodies is inversely correlated with response in prostate cancer

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