Serum Soluble HLA-E in Melanoma: A New Potential Immune-Related Marker in Cancer

Abstract

BackgroundTumor-derived soluble factors, including soluble HLA molecules, can contribute to cancer immune escape and therefore impact on clinical course of malignant diseases. We previously reported that melanoma cells produce, in vitro, soluble forms of the non-classical MHC class I molecule HLA-E (sHLA-E). In order to investigate sHLA-E production by various tumors and to address its potential value as a tumor-associated marker, we developed a specific ELISA for the quantification of sHLA-E in biological fluids.Methodology/Principal FindingsWe developed a sHLA-E specific and sensitive ELISA and we showed that serum sHLA-E levels were significantly elevated (P<0.01) in melanoma patients (n = 127), compared with healthy donors (n = 94). sHLA-E was also detected in the culture supernatants of a wide variety of tumor cell lines (n = 98) including melanomas, kidney, colorectal and breast cancers. Cytokines regulation of sHLA-E production by tumor cells was also carried out. IFN-γ, IFN-α and TNF-α were found to upregulate sHLA-E production by tumor cells.Conclusions/SignificanceIn view of the broad tumor tissue release of HLA-E and its up-regulation by inflammatory cytokines, sHLA-E should be studied for its involvement in immune responses against tumors. Interestingly, our results demonstrated a positive association between the presence of serum sHLA-E and melanoma. Therefore, the determination of sHLA-E levels, using ELISA approach, may be investigated as a clinical marker in cancer patients.

Therapeutic preparations of IVIg contain naturally occurring anti–HLA-E antibodies that react with HLA-Ia (HLA-A/-B/-Cw) alleles

“…45 The sHLA-E occurs without b 2 m. In the intact HLA-E, the presence of b 2 m may mask some of the peptide sequences of the heavy chain. When sHLA-E is devoid of b 2 m, the peptide sequences otherwise masked by b 2 m in intact HLA-E are exposed to elicit an immune response.…”

Soluble HLA-I/Peptide Monomers Mediate Antigen-Specific CD8 T Cell Activation through Passive Peptide Exchange with Cell-Bound HLA-I Molecules

“…We previously reported the ability of both endothelial (19) and tumor cells (20,21) to produce sHLA-E molecules, especially in proinflammatory conditions, and documented a significant increase of serum sHLA-E levels in melanoma patients, compared with healthy donors (20). Moreover, we and others (19,22) observed that naturally produced and recombinant sHLA-E monomers decrease the allogeneic and antitumor activity of NK and CD8 T cells expressing the related inhibitory NK receptor CD94/ NKG2-A.…”

“…The human CMV-reactive CD8 ab T cell clone specific for UL40 [15][16][17][18][19][20][21][22][23] epitope (MART.22) was derived from the PBMCs of a kidney transplant patient (23). The human melanoma-reactive CD8 ab T cell clone specific for NA17-A 1-9 epitope (H2) was derived from peptide-stimulated PBMCs (21).…”

“…80%) used were: HLA-A*0201-binding peptides, NA17-A 1-9 (VLPDVFIRC) (25), and Melan-A [26][27][28][29][30][31][32][33][34][35] (ELAGIGILTV) (26) derived from two human melanomaassociated Ags, HLA-E*0101/03-binding peptides, UL40 [15][16][17][18][19][20][21][22][23] (VMAPRTLLL and VMAPRTLV) derived from human CMV strains (Towne and Toledo) (27,28), and HLA-B*3501-binding self-peptide 37F (LPFDFTPGY) (29). HLA-A*0201/VLPDVFIRC, HLA-A*0201/ELAGIGILTV, HLA-E*0101/ VMAPRTLLL, and HLA-E*0101/VMAPRTLVL monomers were generated by the local recombinant protein facility (SFR Santé, Nantes, France), as previously described (30).…”

“…To this end, experiments were carried out in parallel on two human CD8 T cell clones: a CMV-reactive clone, MART.22, specific for the UL40 [15][16][17][18][19][20][21][22][23] HLA-E-restricted VMAPRTLLL epitope (23), and a melanoma-reactive clone, H2, specific for the NA17-A 1-9 HLA-A*0201-restricted VLPDFIRC epitope (21). To prevent proteolytic degradation of HLA-peptide complexes, all experiments were carried out in serum-free AIM V medium.…”