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The Spontaneous CD8⁺ T-Cell Response to HLA-A2-Restricted NY-ESO-1b Peptide in Hepatocellular Carcinoma Patients

¹ Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China; ² Hepatology Institute and ³ Center of Hepatobiliary Surgery, People’s Hospital, Peking University Health Science Center, Beijing, People’s Republic of China; ⁴ Guangxi Guilin Medical College, Guilin, Guangxi Province, People’s Republic of China; and ⁵ Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, New York

Purpose: Hepatocellular carcinoma (HCC) can express various cancer-testis antigens including NY-ESO-1, members of the SSX family, members of the MAGE family, SCP-1, and CTP11. Immunotherapy directed against these antigens is a potential alternative treatment for HCC. To date, it remains unclear whether HCC patients have spontaneous immune responses to these tumor antigens. The objectives of this study were to measure immune responses to NY-ESO-1, a promising cancer vaccine candidate, in HCC patients using the HLA-A2–restricted NY-ESO-1b peptide (p157-165) to measure cellular responses and whole protein to measure antibody responses.

Experimental Design: In HLA-A2⁺ patients with NY-ESO-1⁺ HCC, we analyzed T-cell antigen-dependent interferon (IFN)- and/or Granzyme B release by enzyme-linked immunospot (ELISPOT) assay and IFN-–producing intracellular cytokine flow cytometry (CytoSpot). As an assay independent of T-cell function, we performed tetramer staining. Antibodies to whole NY-ESO-1 were assayed by enzyme-linked immunosorbent assay.

Results: The frequency of specific CD8⁺ T-cell responses to NY-ESO-1b in 28 NY-ESO-1 mRNA⁺HLA-A2⁺ HCC patients was 35.7% (10 of 28). The average magnitude of effector CD8⁺ T cells was 0.3% (89 ± 59 per 2.5 x 10⁴ CD8⁺ cells) and 1.2% as measured by IFN- release ELISPOT and CytoSpot assays, respectively. These in vitro induced NY-ESO-1b–specific CD8⁺ T cells can also recognize HepG2 cells transfected with pcDNA3.1-NY-ESO-1 in both IFN- and Granzyme B ELISPOT assays. Frequencies of NY-ESO-1b–specific T cells in several patients were confirmed by tetramer staining. Nonfunctional tetramer⁺CD8⁺ T cells were also present. The CD8⁺ T-cell response was apparently increased in patients with late-stage HCC. A discordance between antibody and CD8⁺ T-cell responses in HCC patients was observed.

Conclusions: The elevated frequency of specific CD8⁺ T-cell responses to NY-ESO-1b in NY-ESO-1 mRNA⁺HLA-A2⁺ HCC patients suggests that NY-ESO-1 is appropriate for use in the immunotherapy of HCC patients.