HHLA2, a new immune checkpoint member of the B7 family, is widely expressed in human lung cancer and associated with EGFR mutational status

Haiying Cheng, Murali Janakiram, Alain Borczuk, Juan Lin, Wanglong Qiu, Huijie Liu, Jordan M. Chinai, Balazs Halmos, Roman Perez-Soler, Xingxing Zang

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


Purpose: Immunotherapy with antibodies against B7/CD28 family members, including PD-1, PD-L1, and CTLA-4 has shifted the treatment paradigm for non-small cell lung carcinoma (NSCLC) with improved clinical outcome. HHLA2 is a newly discovered member of the family. By regulating T-cell function, HHLA2 could contribute to tumor immune suppression and thus be a novel target for cancer immunotherapy. There is limited information and critical need to characterize its expression profile and clinical significance in NSCLC. Experimental Design: We performed IHC with an HHLA2-specific antibody (clone 566.1) using tissue microarrays constructed from 679 NSCLC tumor tissues, including 392 cases in the discovery set and 287 cases in the validation cohort. We also studied clinicopathologic characteristics of these patients. Results: Overall, HHLA2 was not detected in most of normal lung tissue but expressed in 66% of NSCLC across different subtypes. In particular, EGFR-mutated NSCLC was significantly associated with higher tumor HHLA2 expression in both discovery (EGFR vs. WT: 76% vs. 53%, P = 0.01) and validation cohorts (89% vs. 69%, P = 0.01). In one of the two cohorts, HHLA2 expression was higher in lung adenocarcinoma as compared with squamous and large cell histology, non-Hispanic White versus Hispanics, and tumors with high tumor-infiltrating lymphocyte (TIL) density. In the multivariate analysis, EGFR mutation status and high TIL intensity were independently associated with HHLA2 expression in lung adenocarcinoma. Conclusions: HHLA2 is widely expressed in NSCLC and is associated with EGFR mutation and high TILs in lung adenocarcinoma. It is potentially a novel target for lung cancer immunotherapy.

Original languageEnglish (US)
Pages (from-to)825-832
Number of pages8
JournalClinical Cancer Research
Issue number3
StatePublished - Feb 1 2017
Externally publishedYes

Bibliographical note

Funding Information:
The work was supported by the NIH Paul Calabresi Career Development Award for Clinical Oncology5K12CA132783-04 (to R. Perez-Soler and H. Cheng), the LUNGevity Foundation Targeted Therapeutics Award (to H. Cheng and B. Halmos), NIHR01CA175495 (to X. Zang), NIHR01DK100525 (to X. Zang), and Department of DefensePC131008 (to X. Zang). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Publisher Copyright:
©2016 AACR.


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