Clinical Pathology

HHLA2 Immune Checkpoint Is a Novel Prognostic Predictor in Hepatocellular Carcinoma



Immunotherapy targeting PD-1/PD-L1 had low response rates and limited overall survival benefits in patients with hepatocellular carcinoma (HCC). We characterized the expression pattern and clinical significance of B7 family immune checkpoint proteins HHLA2, PD-L1, and B7-H4 in HCC.


Immunohistochemistry for HHLA2, PD-L1, B7-H4, CD3, and CD8 was performed on tissue microarray slides from 103 surgically resected HCC specimens.


Positive HHLA2 was detected in 63 (61.2%) cases, with 50 cases showing low expression and 13 cases showing high expression. Positive PD-L1 (combined positive score [CPS] ≥1) was detected in 27 (26.2%) cases, with the majority showing low expression (CPS <10) (n = 25) and only 2 cases showing high expression (CPS ≥10). The coexpression of PD-L1 and HHLA2 was observed in 17 (16.5%) cases. B7-H4 expression was detected in only one (1.0%) case. HHLA2-positive cases had significantly better survival than HHLA2-negative cases (P = .042). Positive HHLA2 correlated with higher density of CD8+ intratumoral lymphocytes (P = .015). The subgroup with both HHLA2 expression and high CD8+ cell density exhibited the most favorable prognosis (P = .036).


HHLA2 is frequently expressed in HCC. Positive HHLA2 correlates with higher CD8+ cell density and favorable prognosis. HHLA2 may be considered a potential therapeutic immune target in HCC.

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