Partial absence of PD-1 expression by tumor-infiltrating EBV-specific CD8⁺ T cells in EBV-driven lymphoepithelioma-like carcinoma.

ABSTRACT:

Objectives

Lymphoepithelioma-like carcinoma (LELC) is an uncommon lung cancer, typically observed in young, non-smoking Asian populations. LELC is associated with Epstein-Barr virus (EBV) infection of lung tumor cells of epithelial origin, suggesting a carcinogenic role of EBV as observed in nasopharyngeal carcinoma (NPC). Here, we studied the antigen specificity and phenotype of EBV-specific CD8⁺ T cells in blood and tumor of one LELC patient positive for EBV infection in lung tumor cells.

Methods

Using multiplex MHC class I tetramers, mass cytometry and mRNA sequencing, we studied EBV-specific CD8⁺ T cells at the transcriptomic and phenotypic levels in blood and tumor tissues of the LELC patient.

Results

Lymphoepithelioma-like carcinoma lung tumor cells were positive for EBV infection. In both blood and tumor tissues, we detected two populations of EBV-specific CD8⁺ T cells targeting the EBV lytic cycle proteins: BRLF1 and BMLF1. Transcriptomic analyses of these two populations in the tumor, which can be considered as tumor-specific, revealed their distinct exhausted profile and polyclonal TCR repertoire. High-dimensional phenotypical analysis revealed the distinct phenotype of these cells between blood and tumor tissues. In tumor tissue, EBV-specific CD8⁺ TILs were phenotypically heterogeneous, but consistently expressed CD39. Unexpectedly, although the LELC tumor cells expressed abundant PD-L1, these tumor-specific CD8⁺ tumor-infiltrating lymphocytes (TILs) mostly did not express PD-1.

Conclusion

Epstein-Barr virus-specific CD8⁺ TILs in EBV-driven tumor are heterogeneous and partially lack PD-1 expression, suggesting that anti-PD1/PD-L1 immunotherapy may not be an appropriate strategy for disinhibiting EBV-specific cells in the treatment of LELC patients.

SUBMITTER: Simoni Y 

PROVIDER: S-EPMC7503213 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature