Human Leukocyte Antigen G Up-Regulation in Lung Cancer Associates with High-Grade Histology, Human Leukocyte Antigen Class I Loss and Interleukin-10 Production

Abstract

Immune evasion in lung cancer results from both structural and functional alterations of human leukocyte antigen (HLA) class I molecules and the local release of immunosuppressive cytokines. Recent data suggest that HLA-G, a nonclassical class Ib molecule, is involved in immune evasion by tumor cells. We sought to determine whether HLA-G could contribute to immunescape in lung cancer. All of 19 tumor specimens examined demonstrated detectable membrane-bound (HLA-G1), as well as soluble (HLA-G5) isoform transcription. Nine of 34 (26%) tumors were positive by immunohistochemistry using monoclonal antibody (mAb) 4H84, recognizing all denatured HLA-G isoforms, of which six were positive using mAb 16G1, recognizing soluble HLA-G. HLA-G immunoreactivity correlated with high-grade histology, with HLA-G being preferentially expressed on large-cell carcinomas. In these patients, loss of classical HLA class I molecules was observed to associate with HLA-G protein up-regulation. Moreover, we found interleukin-10 expressed in 15 of 34 (44%) tumors, and in most of the HLA-G-positive cases (7 of 9), suggesting up-modulation of HLA-G by interleukin-10. It is conceivable that HLA-G expression in lung cancer might be one of the ways how the tumor down-regulates host immune response, in addition to interleukin-10 production and HLA class I loss.

A Soluble Isoform of the Rhesus Monkey Nonclassical MHC Class I Molecule Mamu-AG Is Expressed in the Placenta and the Testis

“…The resulting protein has a novel carboxyl terminus and is able to complex with ␤ 2 -microglobulin, but would be released from the cell due to the lack of a transmembrane domain (12,13). In addition to the placenta (14,34), soluble HLA-G has also been reported in CD4 ϩ T cells (20), activated monocytes (35), thymic epithelium (36), and lung tumor cells (37). It is intriguing that like HLA-G, the Mamu-AG gene also is alternatively spliced to give rise to a soluble molecule.…”

Switch ofHLA-G alternative splicing in a melanoma cell line causes loss of HLA-G1 expression and sensitivity to NK lysis

“…cDNA were prepared from 1-5 lg of total RNA using Ready To Go TM kit and oligo (dT) [12][13][14][15][16][17][18] , according to the manufacturer's recommendations. For HLA-G1 to -G5 transcript detection, PCR amplification and hybridization of the PCR products were performed as previously described.…”

“…1 HLA-G is normally absent on healthy tissues except trophoblast, 2 thymus 3 and cornea. 4 Interestingly, both HLA-G transcription and protein expression are up-regulated on various tumors cells, as demonstrated in biopsies from patients with melanoma, [5][6][7] breast cancer, 8 renal carcinoma, 9,10 primary cutaneous lymphoma, 11 lung cancer, 12 glioma, 13 epithelial cutaneous malignant lesions 14 and colorectal cancer. 15 .…”

Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy

“…[6][7][8][9][10][11] To determine whether the HLA-G 26-40 reactive T cell clones that we generated were capable of recognizing tumor cell, we first evaluated HLA-G expression in some available tumor cell lines (SAS, Calu-1, WiDr, HT29, Lu65, MCF-7, HSC-4 and Jurkat). As shown using Western blot analyses, SAS and Lu65 showed constitutive expression of HLA-G ( With the above information in hand, we proceeded to evaluate the reactivity of the four HLA-G 26-40 reactive T cell clones against HLA-DR and HLA-G expressing tumor cells.…”

“…HLA-G is hardly expressed in normal adult tissues, with the exception of the placenta, where it protects the fetus from the maternal immune system. 4,5 Some tumors such as melanoma, head and neck, lung, urogenital, gastrointestinal and breast cancers express HLA-G, [6][7][8][9][10][11] inhibiting effector immune functions via killer immunoglobulin-like receptor (KIR2DL4) and immunoglobulinlike transcripts, ILT2 and ILT4. [12][13][14] Indeed, HLA-G tumor expression is associated with poor prognosis for some malignancies.…”