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.

PD-1–Expressing Tumor-Infiltrating T Cells Are a Favorable Prognostic Biomarker in HPV-Associated Head and Neck Cancer

“…PD-1 expression on total CD8 or E7 49-57 specific CD8 þ T cells was determined on dissociated cells by cytometry analysis from biopsies of mice tumors (previously vaccinated or not) at a time corresponding to 5 to 6 days after the second vaccination. B, PD-1 expression on total CD8 þ T cells and E7 [49][50][51][52][53][54][55][56][57] -specific CD8 þ T cells in mice vaccinated or not with STxB-E7. PD-1 expression on E7 49-57 -specific CD8 þ T cells from the nonvaccinated group is not shown, as we could not detect these cells in this group.…”

“…They were obtained from PolyPeptide Laboratories (Strasbourg, France), reconstituted in PBS and stored at À20 C. The STxB-E7 [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] vaccine was produced by chemical coupling between the N-bromoacetylated E7 [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] peptide and the sulfhydryl group of STxB-Cys recombinant protein, as previously described (23). After purification, endotoxin concentrations determined by the Limulus assay test (Lonza) were less than 0.5 EU/mg.…”

Myeloma Drug Resistance Induced by Binding of Myeloma B7-H1 (PD-L1) to PD-1

“…In contrast, the expression of programmed cell death 1 (PD-1), which is a member of the CD28 family of molecules and a B7-H1 receptor, is upregulated on tumorinfiltrating T cells, as well as on other activated T cells (4)(5)(6)(7)(8). B7-H1 molecules expressed on tumor cells play a crucial role in tumor evasion from cytotoxic T lymphocyte (CTL)-mediated immune surveillance through PD-1 (9,10).…”

Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

“…In addition, chemotherapy can stimulate anticancer immune effectors either directly (by activating effector or dendritic cells) or indirectly by subverting immunosuppressive mechanisms (18,19). Hence, a recent report pointed out that patients with metastatic melanoma responding to DTIC exhibit a stromal and immune signature, defined by hallmarks of T-cell infiltration and MHC class II expression (20).…”