Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer Journal Article
| Authors: | Matsuzaki, J.; Gnjatic, S.; Mhawech-Fauceglia, P.; Beck, A.; Miller, A.; Tsuji, T.; Eppolito, C.; Qian, F.; Lele, S.; Shrikant, P.; Old, L. J.; Odunsi, K. |
| Article Title: | Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer |
| Abstract: | NY-ESO-1 is a "cancer-testis" antigen frequently expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. In an effort to understand in vivo tolerance mechanisms, we assessed the phenotype and function of NY-ESO-1-specific CD8+ T cells derived from peripheral blood lymphocytes (PBLs), tumor-infiltrating lymphocytes (TILs), and tumor-associated lymphocytes (TALs) of EOC patients with NY-ESO-1-expressing tumors, with or without humoral immunity to NY-ESO-1. Whereas NY-ESO-1-specific CD8+ T cells were readily detectable ex vivo with tetramers in TILs and TALs of seropositive patients, they were only detectable in PBLs following in vitro stimulation. Compared with PBLs, tumor-derived NY-ESO-1-specific CD8+ T cells demonstrated impaired effector function, preferential usage of dominant T-cell receptor, and enriched coexpression of inhibitory molecules LAG-3 and PD-1. Expression of LAG-3 and PD-1 on CD8+ T cells was up-regulated by IL-10, IL-6 (cytokines found in tumor ascites), and tumor-derived antigen-presenting cells. Functionally, CD8+LAG-3+PD-1+ T cells were more impaired in IFN-γ/TNF-α production compared with LAG-3+PD-1 - or LAG-3-PD-1- subsets. Dual blockade of LAG-3 and PD-1 during T-cell priming efficiently augmented proliferation and cytokine production by NY-ESO-1-specific CD8+ T cells, indicating that antitumor function of NY-ESO-1-specific CD8+ T cells could potentially be improved by therapeutic targeting of these inhibitory receptors. |
| Keywords: | signal transduction; controlled study; human tissue; unclassified drug; human cell; ascites; cd8+ t lymphocyte; cell proliferation; tumor associated leukocyte; cd8-positive t-lymphocytes; lymphocytes, tumor-infiltrating; ovarian neoplasms; phenotype; cell function; ovary cancer; interleukin 10; protein; apoptosis regulatory proteins; membrane proteins; gene expression regulation, neoplastic; t lymphocyte receptor; cytokines; antibodies, monoclonal; regulatory mechanism; tumor necrosis factor alpha; antigens, neoplasm; gamma interferon; ny eso 1 antigen; interleukin 6; cytokine production; effector cell; upregulation; antigens, cd; enzyme-linked immunosorbent assay; humoral immunity; peripheral lymphocyte; programmed death 1 receptor; tumor-infiltrating lymphocytes; il-6; t cell receptor; il-10; lymphocyte activation gene 3 protein |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 107 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2010-01-01 |
| Start Page: | 7875 |
| End Page: | 7880 |
| Language: | English |
| DOI: | 10.1073/pnas.1003345107 |
| PUBMED: | 20385810 |
| PROVIDER: | scopus |
| PMCID: | PMC2867907 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 8" - "Export Date: 20 April 2011" - "CODEN: PNASA" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work