Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer

Ganesan, Anusha-Preethi; Clarke, James; Wood, Oliver; Garrido-Martin, Eva M.; Chee, Serena; Mellows, Toby; Samaniego-Castruita, Daniela; Singh, Divya; Seumois, Grégory; Alzetani, Aiman; Woo, E.; Friedmann, Peter S.; King, Emma V.; Thomas, Gareth J.; Sánchez-Elsner, Tilman; Vijayanand, Pandurangan; Ottensmeier, Christian

doi:10.1038/ni.3775

Cited by 403 publications

(474 citation statements)

References 63 publications

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“…Additionally, T RM cells are necessary for the efficacy of cancer vaccine [11, 33]. The protective effect of T RM cells in cancer is linked to their high degree of cytotoxicity, which is correlated with the magnitude of their perforin and granzyme expression [14]. In spite of expressing cytotoxic mediators, T RM cells in the tumour express the exhaustion markers PD‐1, T cell immunoglobulin and mucin domain 3 (TIM‐3) and lymphocyte‐activation gene 3 (LAG‐3) [34].…”

Section: Discussionmentioning

confidence: 99%

“…Notably, the cytotoxic activity of CD8 + T cells is initiated by perforin forming the pore that allows granzymes to enter and induce apoptosis of the tumour cells [13]. In contrast, T RM cells residing in the tumour tissue have been demonstrated to express programmed cell death 1 (PD‐1), suggesting exhaustion [14]. In this context, the phenotype of T RM cells displaying simultaneous cytotoxicity and exhaustion markers needs further study.…”

Section: Introductionmentioning

confidence: 99%

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Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

Hartana

Bergman

Broomé

et al. 2018

Clinical and Experimental Immunology

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SummaryTissue‐resident memory T (TRM) cells are CD8+ T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in TRM cells and correlate it with their functional potential. Fifty‐three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in TRM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in‐vitro stimulation were used to evaluate TRM cell phenotypes. We discovered that tumour TRM cells have low DNA methylation in the PRF1 locus (32·9% methylation), which corresponds to increased numbers of perforin‐expressing TRM cells. Surprisingly, programmed cell death 1 (PD‐1) expression is high in tumour TRM cells, suggesting exhaustion. Following interleukin‐15 and T cell receptor stimulation, perforin and T‐bet expressions are enhanced, indicating that TRM cells from tumours are not terminally exhausted. Moreover, a high number of TRM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, TRM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies TRM cells as potential new targets for cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

Hartana

Bergman

Broomé

et al. 2018

Clinical and Experimental Immunology

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“…Expression by CD8 + CD103 + TIL of granzyme B, perforin and the degranulation marker LAMP-1 (CD107a) was confirmed at the protein level, further supporting their cytotoxic potential [27, 38, 64]. Moreover, in ovarian and lung cancer, T RM cells express the activation marker HLA-DR and the proliferation marker Ki67 [38, 64]. These cells may be functionally exhausted within the tumor microenvironment by the induction of T-cell inhibitory receptors including PD-1 and Tim-3 [27].…”

Section: Mechanisms Of Action Of Trm Cellsmentioning

confidence: 96%

“…T RM cells do not express CCR7, CD62L or S1PR1 [14, 27, 38], which are required for tissue exit (Fig. 1).…”

Section: Phenotypic Features Of Trm Cells In Cancermentioning

confidence: 99%

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Resident memory T cells, critical components in tumor immunology

Mami‐Chouaib¹,

Blanc²,

Corgnac³

et al. 2018

j. immunotherapy cancer

200

186

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CD8+ T lymphocytes are the major anti-tumor effector cells. Most cancer immunotherapeutic approaches seek to amplify cytotoxic T lymphocytes (CTL) specific to malignant cells. A recently identified subpopulation of memory CD8+ T cells, named tissue-resident memory T (TRM) cells, persists in peripheral tissues and does not recirculate. This T-cell subset is considered an independent memory T-cell lineage with a specific profile of transcription factors, including Runx3+, Notch+, Hobit+, Blimp1+, BATF+, AHR+, EOMESneg and Tbetlow. It is defined by expression of CD103 (αE(CD103)β7) and CD49a (VLA-1 or α1β1) integrins and C-type lectin CD69, which are most likely involved in retention of TRM cells in non-lymphoid tissues, including solid tumors. CD103 binds to the epithelial cell marker E-cadherin, thereby favoring the location and retention of TRM in epithelial tumor regions in close contact with malignant cells. The CD103-E-cadherin interaction is required for polarized exocytosis of lytic granules, in particular, when ICAM-1 expression on cancer cells is missing, leading to target cell death. TRM cells also express high levels of granzyme B, IFNγ and TNFα, supporting their cytotoxic features. Moreover, the local route of immunization targeting tissue dendritic cells (DC), and the presence of environmental factors (i.e. TGF-β, IL-33 and IL-15), promote differentiation of this T-cell subtype. In both spontaneous tumor models and engrafted tumors, natural TRM cells or cancer-vaccine-induced TRM directly control tumor growth. In line with these results, TRM infiltration into various human cancers, including lung cancer, are correlated with better clinical outcome in both univariate and multivariate analyses independently of CD8+ T cells. TRM cells also predominantly express checkpoint receptors such as PD-1, CTLA-4 and Tim-3. Blockade of PD-1 with neutralizing antibodies on TRM cells isolated from human lung cancer promotes cytolytic activity toward autologous tumor cells. Thus, TRM cells appear to represent important components in tumor immune surveillance. Their induction by cancer vaccines or other immunotherapeutic approaches may be critical for the success of these treatments. Several arguments, such as their close contact with tumor cells, dominant expression of checkpoint receptors and their recognition of cancer cells, strongly suggest that they may be involved in the success of immune checkpoint inhibitors in various cancers.

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Single‐cell transcriptomics reveal the intratumoral landscape of infiltrated T‐cell subpopulations in oral squamous cell carcinoma

Chen

Yang

et al. 2021

Molecular Oncology

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Systematic analysis of tumor‐infiltrating lymphocytes is essential for the development of new cancer treatments and the prediction of clinical responses to immunotherapy. Immunomodulatory drugs are used for the treatment of oral squamous cell carcinoma (OSCC), depending on immune infiltration profiles of the tumor microenvironment. In this study, we isolated 11,866 single T cells from tumors and paired adjacent normal tissues of three patients with OSCC. Using single‐cell RNA sequencing, we identified 14 distinct T‐cell subpopulations within the tumors and 5 T‐cell subpopulations in the adjacent normal tissues and delineated their developmental trajectories. Exhausted CD8+ T cells and regulatory CD4+ T cells (CD4+ Tregs) were enriched in OSCC tumors, potentially linked to tumor immunosuppression. Programmed death protein 1 (PD‐1) and cytotoxic T lymphocyte‐associated protein 4 (CTLA4) were identified as marker genes in exhausted CD8+ T cells, whereas forkhead box P3 (FOXP3) and CTLA4 were identified as markers of CD4+ Tregs. Furthermore, our data revealed that thymocyte selection‐associated high‐mobility group box (TOX) may be a key regulator of T‐cell dysfunction in the OSCC microenvironment. Overexpression of TOX upregulated expression of genes related to T‐cell dysfunction. In vitro experiments demonstrated that cytotoxic activity and proliferation efficiency of CD8+ T cells overexpressing PD‐1 or TOX were reduced. Notable, the transcription factor PRDM1 was found to transactivate TOX expression via a binding motif in the TOX promoter. Our findings provide valuable insight into the functional states and heterogeneity of T‐cell populations in OSCC that could advance the development of novel therapeutic strategies.

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Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer

Cited by 403 publications

References 63 publications

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

Resident memory T cells, critical components in tumor immunology

Single‐cell transcriptomics reveal the intratumoral landscape of infiltrated T‐cell subpopulations in oral squamous cell carcinoma

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