Progressive upregulation of PD-1 in primary and metastatic melanomas associated with blunted TCR signaling in infiltrating T lymphocytes

Maxime Chapon, Clotilde Randriamampita, Eve Maubec, Cécile Badoual, Stéphane Fouquet, Shu Fang Wang, Eduardo Marinho, David Farhi, Marylène Garcette, Simon Jacobelli, Alexandre Rouquette, Agnès Carlotti, Angélique Girod, Armelle Prévost-Blondel, Alain Trautmann, Marie Françoise Avril, Nadège Bercovici

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

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    Résumé

    Programmed death-1 (PD-1) is involved in T-cell tolerance to self-antigens. For some cancers, it has been suggested that the expression of a ligand of PD-1, namely PD-L1, could contribute to tumor escape from immune destruction. Nevertheless, the relationship between PD-1 expression on tumor-infiltrating T lymphocytes (TILs), disease stage, and TIL responsiveness is still poorly documented. In this study, we show that freshly isolated CD4+ and CD8+ TILs express substantial levels of PD-1 in primary melanomas. The expression of PD-1 was further increased at later stages in distant cutaneous metastases, especially on CD8+ TILs. The expression of PD-1 ligands was frequent only in metastases, on both tumor cells and tumor-derived myeloid cells. TILs isolated from these cutaneous tumors are poorly reactive ex vivo, with blunted calcium response and IFN-γ production after TCR stimulation. Surprisingly, in distinct parts of a primary melanoma, either invasive or regressing, we show that TILs similarly express PD-1 and remain dysfunctional. The expressions of PD-1 and PD-L1 in metastatic melanoma lesions could be considered as witnesses of an unsuccessful anti-tumoral immune response, but the direct involvement of PD-1 in the severity of the disease, and the importance of TILs in tumor regression, remain to be established.

    langue originaleAnglais
    Pages (de - à)1300-1307
    Nombre de pages8
    journalJournal of Investigative Dermatology
    Volume131
    Numéro de publication6
    Les DOIs
    étatPublié - 1 janv. 2011

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