title: BTLA identifies dysfunctional PD-1-expressing CD4+T cells in human hepatocellular carcinoma.
abstract: Although immunotherapy targeting programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway is being applied in clinic, the response outcomes are heterogeneous, suggesting existences of distinctive subsets within PD-1-expressing T cells that react differently to PD-1/PD-L1 blockade. However, markers to demarcate these subsets in human cancers remain unclear. Here, we found that both PD-1 and B and T lymphocyte attenuator (BTLA) were significantly upregulated on CD4+T cells from tumor compared with those from paired non-tumor liver in hepatocellular carcinoma (HCC) patients. Interestingly, over 85% BTLA+CD4+T cells were PD-1-expressing cells and represented about 50% PD-1+CD4+T cells in tumors, and that level of BTLA+PD-1+tumor CD4+T cells were selectively associated with advanced stage HCC. BTLA+identified highly dysfunctional PD-1-expressing CD4+T cell subset, whereas BTLA-defined PD-1+CD4+T cells undergoing activation in HCC. Importantly, blockade of PD-L1 could restore the ability of IFNγ/TNF-α production in BTLA+PD-1+tumor CD4+T cells but partially suppressed the activation of BTLA-PD-1+CD4+T cells. Moreover, we provided evidence that BTLA signals also participated in suppressing CD4+T cell function in HCC. In conclusion, BTLA could identify distinct function of PD-1 expressing CD4+T cells in human cancer, which might not only advance our understanding of inhibitory receptor blockade, but also provide new targets for clinical predictors of response to these immunotherapies.
authors.affiliation: Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China; Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Qiyi
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University , Guangzhou, P.R. China.
authors.forename: Zhan-Lian
authors.initials: ZL
authors.lastname: Huang
authors.affiliation: Department of Clinical Diagnosis, Guangdong Provincial Hospital of Chinese Medicine , Guangzhou, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University , Guangzhou, P.R. China.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China; Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Kuang
keywords: BTLA; HCC; co-expression; helper T cells; programmed cell death 1