Induction of resident memory T cells enhances the efficacy of cancer vaccine

Nizard, Mevyn; Roussel, H.; Diniz, Mariana O.; Karaki, Soumaya; Tran, Thi; Voron, Thibault; Dransart, Estelle; Sandoval, Fédérico; Riquet, Marc; Rance, Bastien; Marcheteau, Elie; Fabre, Elizabeth; Mandavit, Marion; Terme, Magali; Blanc, Charlotte; Escudié, Jean-Baptiste; Gibault, Laure; Barthes, F. Le Pimpec; Granier, Clémence; Ferreira, Luís Carlos S.; Badoual, Cécile; Johannes, Ludger; Tartour, Éric

doi:10.1038/ncomms15221

Cited by 218 publications

(241 citation statements)

References 45 publications

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“…Similar results were obtained by Murray et al, using anti-CD49a mAb in a melanoma model [83]. In one of our group's study, the co-administration of an anti-TGF-β antibody with the vaccine reduced the number of T RM cells and control of tumor growth by the vaccine [39]. By blocking recruitment of effector T cells arising from the lymphoid organs with the FTY720 drug, which downmodulates the S1PR1 molecule, it has been demonstrated that T RM cells induced by intranasal vaccination are able to control tumors [39].…”

Section: Role Of Trm In Immune Surveillance and Immunotherapysupporting

confidence: 85%

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Resident memory T cells, critical components in tumor immunology

Mami‐Chouaib¹,

Blanc²,

Corgnac³

et al. 2018

j. immunotherapy cancer

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193

155

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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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Section: Role Of Trm In Immune Surveillance and Immunotherapysupporting

confidence: 85%

“…These cells are also found in various tumors, including melanoma [78], lung cancer [27, 39], urothelial cell carcinoma [29] and endometrial adenocarcinoma [79]. Tumors with a high density of CD8 + T cells showed enrichment for transcripts linked to tissue-T-cell-residency, such as CD103 [38].…”

Section: Role Of Trm In Immune Surveillance and Immunotherapymentioning

confidence: 99%

Resident memory T cells, critical components in tumor immunology

Mami‐Chouaib¹,

Blanc²,

Corgnac³

et al. 2018

j. immunotherapy cancer

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193

155

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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].…”

Section: Discussionmentioning

confidence: 99%

“…The improved prognosis is due to the capacity of T RM cells to produce IFN‐γ upon in‐situ antigen recognition [11], resulting in the recruitment of circulating T cells from the blood [12]. Furthermore, the cytotoxic capacity of T RM cells against tumour cells is demonstrated by their production of the cytotoxic mediators, perforin, granzyme A, and granzyme B upon CD103/E‐cadherin ligation and T cell receptor (TCR) activation [8].…”

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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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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“…70 73 Finally, another population called resident memory T cells, which persist in tumour tissue, isrequired for the efficacy of certain immunotherapeutic approaches. 78 This population, identified by CD103 and CD49a markers, expressed PD-1 and preferentially recognised tumour cells compared with conventional circulating effector CD8 + T cells.…”

Section: Blockade Of Intrinsic Tumour Signalling Mediated By Pd-l1mentioning

confidence: 96%

Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer

et al. 2017

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The large family of costimulatory molecules plays a crucial role in regulation of the immune response. These molecules modulate TCR signalling via phosphorylation cascades. Some of the coinhibitory members of this family, such as PD-1 and CTLA-4, already constitute approved targets in cancer therapy and, since 2011, have opened a new area of antitumour immunotherapy. Many antibodies targeting other inhibitory receptors (Tim-3, VISTA, Lag-3 and so on) or activating costimulatory molecules (OX40, GITR and so on) are under evaluation. These antibodies have multiple mechanisms of action. At the cellular level, these antibodies restore the activation signalling pathway and reprogram T cell metabolism. Tumour cells become resistant to apoptosis when an intracellular PD-L1 signalling is blocked. CD8+ T cells are considered to be the main effectors of the blockade of inhibitory receptors. Certain CD8+ T cell subsets, such as non-hyperexhausted (CD28+, T-bethigh, PD-1int), follicular-like (CXCR-5+) or resident memory CD8+ T cells, are more prone to be reactivated by anti-PD-1/PD-L1 monoclonal antibody (mAb). In the future, the challenge will be to rationally combine drugs able to make the tumour microenvironment more permissive to immunotherapy in order to potentiate its clinical activity.

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Induction of resident memory T cells enhances the efficacy of cancer vaccine

Cited by 218 publications

References 45 publications

Resident memory T cells, critical components in tumor immunology

Resident memory T cells, critical components in tumor immunology

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

Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer

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