Wide expression and significance of alternative immune checkpoint molecules, B7x and HHLA2, in PD-L1–negative human lung cancers

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Abstract

Purpose: Immunotherapy targeting the PD-1/PD-L1 pathway has changed the treatment landscape of non–small cell lung carcinoma (NSCLC). We demonstrated that HHLA2, a newly identified immune inhibitory molecule, was widely expressed in NSCLC. We now compared the expression and function of PD-L1 with alternative immune checkpoints, B7x and HHLA2. Experimental Design: Expression was examined in tissue microarrays consisting of 392 resected NSCLC tumors. Effects of PD-L1, B7x, and HHLA2 on human T-cell proliferation and cytokine production were investigated. Results: PD-L1 expression was identified in 25% and 31% of tumors in the discovery and validation cohorts and was associated with higher stage and lymph node involvement. The multivariate analysis showed that stage, TIL status, and lymph node involvement were independently associated with PD-L1 expression. B7x was expressed in 69% and 68%, whereas HHLA2 was positive in 61% and 64% of tumors in the two sets. The coexpression of PD-L1 with B7x or HHLA2 was infrequent, 6% and 3%. The majority (78%) of PD-L1–negative cases expressed B7x, HHLA2, or both. The triple-positive group had more TIL infiltration than the triple-negative group. B7x-Ig and HHLA2-Ig inhibited TCR-mediated proliferation of CD4 and CD8 T cells more robustly than PD-L1-Ig. All three significantly suppressed cytokine productions by T cells. Conclusions: The majority of PD-L1–negative lung cancers express alternative immune checkpoints. The roles of the B7x and HHLA2 pathway in mediating immune evasion in PD-L1–negative tumors deserve to be explored to provide the rationale for an effective immunotherapy strategy in these tumors.

Original languageEnglish (US)
Pages (from-to)1954-1964
Number of pages11
JournalClinical Cancer Research
Volume24
Issue number8
DOIs
StatePublished - Apr 15 2018

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Lung Neoplasms
Neoplasms
Carcinoma
T-Lymphocytes
Immunotherapy
Lung
Lymph Nodes
Cytokines
Immune Evasion
Research Design
Multivariate Analysis
Cell Proliferation
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{b830d8b1e46747c8a70a0065c5aa1295,
title = "Wide expression and significance of alternative immune checkpoint molecules, B7x and HHLA2, in PD-L1–negative human lung cancers",
abstract = "Purpose: Immunotherapy targeting the PD-1/PD-L1 pathway has changed the treatment landscape of non–small cell lung carcinoma (NSCLC). We demonstrated that HHLA2, a newly identified immune inhibitory molecule, was widely expressed in NSCLC. We now compared the expression and function of PD-L1 with alternative immune checkpoints, B7x and HHLA2. Experimental Design: Expression was examined in tissue microarrays consisting of 392 resected NSCLC tumors. Effects of PD-L1, B7x, and HHLA2 on human T-cell proliferation and cytokine production were investigated. Results: PD-L1 expression was identified in 25{\%} and 31{\%} of tumors in the discovery and validation cohorts and was associated with higher stage and lymph node involvement. The multivariate analysis showed that stage, TIL status, and lymph node involvement were independently associated with PD-L1 expression. B7x was expressed in 69{\%} and 68{\%}, whereas HHLA2 was positive in 61{\%} and 64{\%} of tumors in the two sets. The coexpression of PD-L1 with B7x or HHLA2 was infrequent, 6{\%} and 3{\%}. The majority (78{\%}) of PD-L1–negative cases expressed B7x, HHLA2, or both. The triple-positive group had more TIL infiltration than the triple-negative group. B7x-Ig and HHLA2-Ig inhibited TCR-mediated proliferation of CD4 and CD8 T cells more robustly than PD-L1-Ig. All three significantly suppressed cytokine productions by T cells. Conclusions: The majority of PD-L1–negative lung cancers express alternative immune checkpoints. The roles of the B7x and HHLA2 pathway in mediating immune evasion in PD-L1–negative tumors deserve to be explored to provide the rationale for an effective immunotherapy strategy in these tumors.",
author = "Haiying Cheng and Alain Borczuk and Murali Janakiram and Xiaoxin Ren and Juan Lin and Amer Assal and Balazs Halmos and Roman Perez-Soler and Xingxing Zang",
year = "2018",
month = "4",
day = "15",
doi = "10.1158/1078-0432.CCR-17-2924",
language = "English (US)",
volume = "24",
pages = "1954--1964",
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issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
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TY - JOUR

T1 - Wide expression and significance of alternative immune checkpoint molecules, B7x and HHLA2, in PD-L1–negative human lung cancers

AU - Cheng, Haiying

AU - Borczuk, Alain

AU - Janakiram, Murali

AU - Ren, Xiaoxin

AU - Lin, Juan

AU - Assal, Amer

AU - Halmos, Balazs

AU - Perez-Soler, Roman

AU - Zang, Xingxing

PY - 2018/4/15

Y1 - 2018/4/15

N2 - Purpose: Immunotherapy targeting the PD-1/PD-L1 pathway has changed the treatment landscape of non–small cell lung carcinoma (NSCLC). We demonstrated that HHLA2, a newly identified immune inhibitory molecule, was widely expressed in NSCLC. We now compared the expression and function of PD-L1 with alternative immune checkpoints, B7x and HHLA2. Experimental Design: Expression was examined in tissue microarrays consisting of 392 resected NSCLC tumors. Effects of PD-L1, B7x, and HHLA2 on human T-cell proliferation and cytokine production were investigated. Results: PD-L1 expression was identified in 25% and 31% of tumors in the discovery and validation cohorts and was associated with higher stage and lymph node involvement. The multivariate analysis showed that stage, TIL status, and lymph node involvement were independently associated with PD-L1 expression. B7x was expressed in 69% and 68%, whereas HHLA2 was positive in 61% and 64% of tumors in the two sets. The coexpression of PD-L1 with B7x or HHLA2 was infrequent, 6% and 3%. The majority (78%) of PD-L1–negative cases expressed B7x, HHLA2, or both. The triple-positive group had more TIL infiltration than the triple-negative group. B7x-Ig and HHLA2-Ig inhibited TCR-mediated proliferation of CD4 and CD8 T cells more robustly than PD-L1-Ig. All three significantly suppressed cytokine productions by T cells. Conclusions: The majority of PD-L1–negative lung cancers express alternative immune checkpoints. The roles of the B7x and HHLA2 pathway in mediating immune evasion in PD-L1–negative tumors deserve to be explored to provide the rationale for an effective immunotherapy strategy in these tumors.

AB - Purpose: Immunotherapy targeting the PD-1/PD-L1 pathway has changed the treatment landscape of non–small cell lung carcinoma (NSCLC). We demonstrated that HHLA2, a newly identified immune inhibitory molecule, was widely expressed in NSCLC. We now compared the expression and function of PD-L1 with alternative immune checkpoints, B7x and HHLA2. Experimental Design: Expression was examined in tissue microarrays consisting of 392 resected NSCLC tumors. Effects of PD-L1, B7x, and HHLA2 on human T-cell proliferation and cytokine production were investigated. Results: PD-L1 expression was identified in 25% and 31% of tumors in the discovery and validation cohorts and was associated with higher stage and lymph node involvement. The multivariate analysis showed that stage, TIL status, and lymph node involvement were independently associated with PD-L1 expression. B7x was expressed in 69% and 68%, whereas HHLA2 was positive in 61% and 64% of tumors in the two sets. The coexpression of PD-L1 with B7x or HHLA2 was infrequent, 6% and 3%. The majority (78%) of PD-L1–negative cases expressed B7x, HHLA2, or both. The triple-positive group had more TIL infiltration than the triple-negative group. B7x-Ig and HHLA2-Ig inhibited TCR-mediated proliferation of CD4 and CD8 T cells more robustly than PD-L1-Ig. All three significantly suppressed cytokine productions by T cells. Conclusions: The majority of PD-L1–negative lung cancers express alternative immune checkpoints. The roles of the B7x and HHLA2 pathway in mediating immune evasion in PD-L1–negative tumors deserve to be explored to provide the rationale for an effective immunotherapy strategy in these tumors.

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U2 - 10.1158/1078-0432.CCR-17-2924

DO - 10.1158/1078-0432.CCR-17-2924

M3 - Article

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SP - 1954

EP - 1964

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

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