title: Progressive upregulation of PD-1 in primary and metastatic melanomas associated with blunted TCR signaling in infiltrating T lymphocytes.
abstract: 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.
authors.affiliation: Institut Cochin, Inserm, U1016, Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Chapon
authors.forename: Clotilde
authors.initials: C
authors.lastname: Randriamampita
authors.forename: Eve
authors.initials: E
authors.lastname: Maubec
authors.forename: Cécile
authors.initials: C
authors.lastname: Badoual
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fouquet
authors.forename: Shu-Fang
authors.initials: SF
authors.lastname: Wang
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marinho
authors.forename: David
authors.initials: D
authors.lastname: Farhi
authors.forename: Marylène
authors.initials: M
authors.lastname: Garcette
authors.forename: Simon
authors.initials: S
authors.lastname: Jacobelli
authors.forename: Alexandre
authors.initials: A
authors.lastname: Rouquette
authors.forename: Agnès
authors.initials: A
authors.lastname: Carlotti
authors.forename: Angélique
authors.initials: A
authors.lastname: Girod
authors.forename: Armelle
authors.initials: A
authors.lastname: Prévost-Blondel
authors.forename: Alain
authors.initials: A
authors.lastname: Trautmann
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Avril
authors.forename: Nadège
authors.initials: N
authors.lastname: Bercovici
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000032:analysis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000502:physiology*; D018122:B7-1 Antigen / Q000032:analysis; D060890:B7-H1 Antigen; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000556:secondary; D008875:Middle Aged; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D011446:Prospective Studies; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell