PD-L2 expression in human tumors: Relevance to anti-PD-1 therapy in cancer

Jennifer H. Yearley, Christopher Gibson, Ni Yu, Christina Moon, Erin Murphy, Jonathan Juco, Jared Lunceford, Jonathan Cheng, Laura Q.M. Chow, Tanguy Lim Seiwert, Masahisa Handa, Joanne E. Tomassini, Terrill McClanahan

Research output: Contribution to journalArticle

Abstract

Purpose: Tumor-associated PD-L1 expression is predictive of clinical response to PD-1-directed immunotherapy. However, PD-L1-negative patients may also respond to PD-1 checkpoint blockade, suggesting that other PD-1 ligands may be relevant to the clinical activity of these therapies. The prevalence of PD-L2, the other known ligand of PD-1, and its relationship to response to anti-PD-1 therapy were evaluated. Experimental Design: PD-L2 expression was assessed in archival tumor tissue from seven indications using a novel immunohistochemical assay. In addition, relationships between clinical response and PD-L2 status were evaluated in tumor tissues from patients with head and neck squamous cell carcinoma (HNSCC) with recurrent or metastatic disease, treated with pembrolizumab. Results: PD-L2 expression was observed in all tumor types and present in stromal, tumor, and endothelial cells. The prevalence and distribution of PD-L2 correlated significantly with PD-L1 (P = 0.0012-<0.0001); however, PD-L2 was detected in the absence of PD-L1 in some tumor types. Both PD-L1 and PD-L2 positivity significantly predicted clinical response to pembrolizumab on combined tumor, stromal and immune cells, with PD-L2 predictive independent of PD-L1. Response was greater in patients positive for both PD-L1 and PD-L2 (27.5%) than those positive only for PD-L1 (11.4%). PD-L2 status was also a significant predictor of progression-free survival (PFS) with pembrolizumab independent of PD-L1 status. Longer median times for PFS and overall survival were observed for PD-L2-positive than PD-L2-negative patients. Conclusions: Clinical response to pembrolizumab in patients with HNSCC may be related partly to blockade of PD-1/PD-L2 interactions. Therapy targeting both PD-1 ligands may provide clinical benefit in these patients.

Original languageEnglish (US)
Pages (from-to)3158-3167
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number12
DOIs
StatePublished - Jun 15 2017
Externally publishedYes

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Neoplasms
Stromal Cells
Ligands
Therapeutics
Disease-Free Survival
Immunotherapy
Research Design
Endothelial Cells
Survival
pembrolizumab
Carcinoma, squamous cell of head and neck

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Yearley, J. H., Gibson, C., Yu, N., Moon, C., Murphy, E., Juco, J., ... McClanahan, T. (2017). PD-L2 expression in human tumors: Relevance to anti-PD-1 therapy in cancer. Clinical Cancer Research, 23(12), 3158-3167. https://doi.org/10.1158/1078-0432.CCR-16-1761

PD-L2 expression in human tumors : Relevance to anti-PD-1 therapy in cancer. / Yearley, Jennifer H.; Gibson, Christopher; Yu, Ni; Moon, Christina; Murphy, Erin; Juco, Jonathan; Lunceford, Jared; Cheng, Jonathan; Chow, Laura Q.M.; Lim Seiwert, Tanguy; Handa, Masahisa; Tomassini, Joanne E.; McClanahan, Terrill.

In: Clinical Cancer Research, Vol. 23, No. 12, 15.06.2017, p. 3158-3167.

Research output: Contribution to journalArticle

Yearley, JH, Gibson, C, Yu, N, Moon, C, Murphy, E, Juco, J, Lunceford, J, Cheng, J, Chow, LQM, Lim Seiwert, T, Handa, M, Tomassini, JE & McClanahan, T 2017, 'PD-L2 expression in human tumors: Relevance to anti-PD-1 therapy in cancer', Clinical Cancer Research, vol. 23, no. 12, pp. 3158-3167. https://doi.org/10.1158/1078-0432.CCR-16-1761
Yearley, Jennifer H. ; Gibson, Christopher ; Yu, Ni ; Moon, Christina ; Murphy, Erin ; Juco, Jonathan ; Lunceford, Jared ; Cheng, Jonathan ; Chow, Laura Q.M. ; Lim Seiwert, Tanguy ; Handa, Masahisa ; Tomassini, Joanne E. ; McClanahan, Terrill. / PD-L2 expression in human tumors : Relevance to anti-PD-1 therapy in cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 12. pp. 3158-3167.
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abstract = "Purpose: Tumor-associated PD-L1 expression is predictive of clinical response to PD-1-directed immunotherapy. However, PD-L1-negative patients may also respond to PD-1 checkpoint blockade, suggesting that other PD-1 ligands may be relevant to the clinical activity of these therapies. The prevalence of PD-L2, the other known ligand of PD-1, and its relationship to response to anti-PD-1 therapy were evaluated. Experimental Design: PD-L2 expression was assessed in archival tumor tissue from seven indications using a novel immunohistochemical assay. In addition, relationships between clinical response and PD-L2 status were evaluated in tumor tissues from patients with head and neck squamous cell carcinoma (HNSCC) with recurrent or metastatic disease, treated with pembrolizumab. Results: PD-L2 expression was observed in all tumor types and present in stromal, tumor, and endothelial cells. The prevalence and distribution of PD-L2 correlated significantly with PD-L1 (P = 0.0012-<0.0001); however, PD-L2 was detected in the absence of PD-L1 in some tumor types. Both PD-L1 and PD-L2 positivity significantly predicted clinical response to pembrolizumab on combined tumor, stromal and immune cells, with PD-L2 predictive independent of PD-L1. Response was greater in patients positive for both PD-L1 and PD-L2 (27.5{\%}) than those positive only for PD-L1 (11.4{\%}). PD-L2 status was also a significant predictor of progression-free survival (PFS) with pembrolizumab independent of PD-L1 status. Longer median times for PFS and overall survival were observed for PD-L2-positive than PD-L2-negative patients. Conclusions: Clinical response to pembrolizumab in patients with HNSCC may be related partly to blockade of PD-1/PD-L2 interactions. Therapy targeting both PD-1 ligands may provide clinical benefit in these patients.",
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AU - Yearley, Jennifer H.

AU - Gibson, Christopher

AU - Yu, Ni

AU - Moon, Christina

AU - Murphy, Erin

AU - Juco, Jonathan

AU - Lunceford, Jared

AU - Cheng, Jonathan

AU - Chow, Laura Q.M.

AU - Lim Seiwert, Tanguy

AU - Handa, Masahisa

AU - Tomassini, Joanne E.

AU - McClanahan, Terrill

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N2 - Purpose: Tumor-associated PD-L1 expression is predictive of clinical response to PD-1-directed immunotherapy. However, PD-L1-negative patients may also respond to PD-1 checkpoint blockade, suggesting that other PD-1 ligands may be relevant to the clinical activity of these therapies. The prevalence of PD-L2, the other known ligand of PD-1, and its relationship to response to anti-PD-1 therapy were evaluated. Experimental Design: PD-L2 expression was assessed in archival tumor tissue from seven indications using a novel immunohistochemical assay. In addition, relationships between clinical response and PD-L2 status were evaluated in tumor tissues from patients with head and neck squamous cell carcinoma (HNSCC) with recurrent or metastatic disease, treated with pembrolizumab. Results: PD-L2 expression was observed in all tumor types and present in stromal, tumor, and endothelial cells. The prevalence and distribution of PD-L2 correlated significantly with PD-L1 (P = 0.0012-<0.0001); however, PD-L2 was detected in the absence of PD-L1 in some tumor types. Both PD-L1 and PD-L2 positivity significantly predicted clinical response to pembrolizumab on combined tumor, stromal and immune cells, with PD-L2 predictive independent of PD-L1. Response was greater in patients positive for both PD-L1 and PD-L2 (27.5%) than those positive only for PD-L1 (11.4%). PD-L2 status was also a significant predictor of progression-free survival (PFS) with pembrolizumab independent of PD-L1 status. Longer median times for PFS and overall survival were observed for PD-L2-positive than PD-L2-negative patients. Conclusions: Clinical response to pembrolizumab in patients with HNSCC may be related partly to blockade of PD-1/PD-L2 interactions. Therapy targeting both PD-1 ligands may provide clinical benefit in these patients.

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