Vitiligo is a chronic autoimmune depigmenting skin disorder that results from a loss of melanocytes. Multiple combinatorial factors have been involved in disease development, with a prominent role of the immune system, in particular T cells. After repigmentation, vitiligo frequently recurs in the same area, suggesting that vitiligo could involve the presence of resident memory T cells (T). We sought to perform a thorough characterization of the phenotype and function of skin memory T cells in vitiligo. We show that stable and active vitiligo perilesional skin is enriched with a population of CD8 T expressing both CD69 and CD103 compared with psoriasis and control unaffected skin. CD8 T expressing CD103 are mainly localized in the epidermis. Expression of CXCR3 is observed on most CD8 T in vitiligo, including the population of melanocyte-specific CD8 T cells. CD8 T displayed increased production of IFN-γ and tumor necrosis factor-α with moderate cytotoxic activity. Our study highlights the presence of functional CD8 T in both stable and active vitiligo, reinforcing the concept of vitiligo as an immune memory skin disease. The CD8 T that remain in stable disease could play a role during disease flares, emphasizing the interest in targeting this cell subset in vitiligo.

Epithelial ovarian cancer (EOC) usually spreads into the peritoneal cavity, thereby providing an opportunity for intraperitoneal adoptive immunotherapy with Vc9Vd2 T lymphocytes, a T cell subpopulation endowed with high lytic properties against tumor cells. However, previous studies have reported that Vc9Vd2 T cells fail to expand from peripheral blood mononuclear cells in one-third of patients with cancer. Here, from a cohort of 37 patients with EOC, a multiple correspondence analysis identified three populations, one of which was not suitable for Vc9Vd2 T-cell adoptive therapy. Interestingly, the ineligible patients were identified based on the frequency of Vc9Vd2 T cells in their peripheral blood and the patients' age. The average time to tumor recurrence was also found to be significantly different between the three populations, suggesting that the innate immune response is involved in EOC prognosis. A dramatic decrease in the lytic properties of Vc9Vd2 T cells occurred following incubation with ascitic supernatant and was found to be associated with reduced perforin/granzyme degranulation. Prostaglandin E2, but not IL-6, IL-10, VEGF or TGF-b, showed immunosuppressive effects in Vc9Vd2 T cells. Interestingly, our results emphasize that pretreating ovarian tumor cells with zoledronate partially reverses the immunosuppressive effects of ovarian cancer-associated ascites and restores a high level of lytic activity. These data sustain that optimal Vc9Vd2 T-cell adoptive immunotherapy previously requires counteracting the tumor immunosuppressive microenvironment. Altogether, our findings provide a rationale for clinically evaluating Vc9Vd2 T-cell adoptive immunotherapy with intraperitoneal carcinomatosis presensitization by zoledronate in patients with EOC.Epithelial ovarian cancer (EOC) is the fifth most frequent cancer among women and the fourth most common cause of cancer-related deaths among women.1 More than 70% of patients are diagnosed when the cancer has spread beyond the ovaries, and these patients have low median survival rates.2 The prognosis is poor, with a 5-year survival rate of only 30%, and the rate is less than 10% for patients with bulky residual disease remaining after surgery and chemotherapy, which emphasizes the need for innovative treatments.3 The inflammatory microenvironment of ovarian carcinomas prevents the maturation of myeloid cells, favors regulatory T-cell development and restrains the cytotoxic activity of effector T lymphocytes, leading to the escape of the tumor from the immune system. 4 Thus, research is ongoing to develop innovative approaches aimed at stimulating the immune system. 5 The preferential spread pattern of EOC in the peritoneal cavity offers an excellent opportunity for the regional administration of adoptive T-cell therapy.2 Some pilot trials have shown the feasibility of and promising

Human Vγ9Vδ2 T cells exert potent in vitro and in vivo antitumor activities, making them promising candidates for immunotherapy strategies. Recognition of tumor cells by Vγ9Vδ2 T cells requires engagement of the TCR and/or NK receptors. Recently, one of the novel NK receptors, the class I–restricted T cell–associated molecule (CRTAM), has been described to promote cytotoxic function of NK cells and to lead to IFN-γ secretion by CD8+ T cells through interaction with its ligand, Necl-2. A better understanding of the role of CRTAM in Vγ9Vδ2 T cell functions is highly relevant to optimize innate-like T cell–based cancer immunotherapy. In this article, we report that CRTAM is transiently expressed on activated Vγ9Vδ2 T lymphocytes following TCR engagement. However, CRTAM–Necl-2 interaction does not modify the cytotoxic function or IFN-γ secretion of Vγ9Vδ2 T cells. The expression of CRTAM in activated Vγ9Vδ2 T cells is quickly downregulated following interaction with Necl-2 on tumor cells. Of interest, CRTAM is concurrently acquired at the cell surface of Necl-2+ tumor cells through Vγ9Vδ2 T cell membrane capture. Finally, we highlight that coculture experiments with tumor cells expressing Necl-2 result in significant cell death of CRTAM+ Vγ9Vδ2 T cells. CRTAM-mediated cell death is dependent on an autophagic process, but not on apoptosis or necroptosis, as attested by the expression of characteristic markers and blocking experiments with specific inhibitors. On the basis of these findings, we propose that Necl-2 on tumor cells represents a new tumor counterattack mechanism and a potential target to improve efficiency of γδ T cell–based immunotherapy.

Historiquement, PVR (poliovirus receptor) (CD155), aujourd'hui dénommée nectine-like 5 (Necl-5), est la première molécule de la famille des nectines/nectines-like à avoir été caractérisée : c'est le récepteur d'entrée du poliovirus humain. Nectine-1 et nectine-2 ont été les premières nectines isolées, et leur rôle de récepteur dans l'internalisation des virus herpes simplex 1 et 2 a ensuite été démontré. Actuellement, quatre nectines (nectine-1 à -4) et cinq molécules apparentées aux nectines (Necl-1 à -5) ont été identifiées. Leur nomenclature est compliquée du fait que chaque nectine/nectine-like possède plusieurs appellations (voir pour revue [2]). Par exemple, nectine-1 est parfois appelée PRR1 (poliovirus receptor-related protein) ou HVEC (herpes virus entry mediator C). Il faut noter que nectine-4, aussi appelée PVLR4 (poliovirus-receptor-like 4), est éga-lement un des récepteurs d'entrée du virus de la rougeole [3]. Pour Necl-2, plusieurs appellations existent selon la situation biologique dans laquelle son expression a été recherchée : TSLC1 (tumor suppressor in lung cancer 1), IGSF4 (immunoglobulin superfamily member 4), Ra175, SglGSF (spermatogenic immunoglobulin superfamily), ou Syn-CAM1 (synaptic cell adhesion molecule 1). Toutes ces molécules ont une structure similaire ( Figure 1A). Les trois domaines de type Ig-like de la portion extracellulaire -un de type V et deux de type C2 -sont responsables des interactions homophiliques et hétérophiliques des nectines/nectines-like entre elles ou avec leurs ligands, ainsi que de leur dimérisation ( Figure 1B) Les nectines/nectines-like et leurs ligandsLes nectines et nectines-like (Necl) sont des molé-cules dont le nom vient du terme latin necto qui signifie connecter. Elles appartiennent à la superfamille des immunoglobulines (Ig) et ont été initialement décrites pour leur rôle dans les processus d'adhérence indépendants du Ca 2+ [1]. Ce sont des partenaires importants de la formation des jonctions cellulaires dans les tissus épithéliaux et elles participent éga-lement à la polarité cellulaire [2]. Leurs rôles dans la migration cellulaire, l'inhibition de contact, puis la prolifération et la différenciation ont été décrits secondairement. Récemment, la corrélation entre leur surexpression dans les tumeurs ou, au contraire, la perte de leur expression, et le pronostic de ces

Vγ9Vδ2 cells are cytotoxic T cells that are able to recognize epithelial ovarian carcinoma (EOC) cells. Therefore, Vγ9Vδ2 cell-based adoptive transfer is an attractive therapy for EOC. However, the inefficient ex vivo expansion after specific stimulation of Vγ9Vδ2 cells from some patients and the relationships between Vγ9Vδ2 cells and clinical course of EOC are issues that remain to be clarified. Herein, peripheral blood mononuclear cells (PBMCs) from 60 EOC patients were stimulated with bromohydrin pyrophosphate (BrHPP) or zoledronate, which are specific agonists of Vγ9Vδ2 cells. The compounds differed in their efficacies to induce ex vivo Vγ9Vδ2 PBMC expansion, but 16/60 samples remained inefficiently expanded with both stimuli. Interestingly, the Vγ9Vδ2 cells in these low-responding PBMCs displayed before expansion (ex vivo PBMCs) an altered production of the pro-inflammatory cytokines IFN-γ and TNF-α, a decreased naive fraction and a reduced frequency. No evidence of an involvement of CD4+CD25+Foxp3+ regulatory cells was observed. Importantly, our data also demonstrate that a Vγ9Vδ2 cell frequency of 0.35% or less in EOC PBMCs could be used to predict low responses to both BrHPP and zoledronate. Moreover, our data highlight that such a deficiency is not correlated with advanced EOC stages but is associated with more refractory states to platinum-based chemotherapy and is an independent predictor of shorter disease-free survival after treatment. These results are the first to suggest a potential contribution of Vγ9Vδ2 cells to the anti-tumor effects of chemotherapeutic agents and they strengthen interest in strategies that might increase Vγ9Vδ2 cells in cancer patients.

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