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Cancer Immunol Immunother. 2019 Mar;68(3):421-432. doi: 10.1007/s00262-018-2282-1. Epub 2018 Dec 18.

A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Boston, MA, 02215, USA.
2
Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
3
Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, 02142, USA.
4
Department of Medicine, University of North Carolina Kidney Center, Chapel Hill, NC, 27599, USA.
5
Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, 02114, USA.
6
Neon Therapeutics Inc., Cambridge, MA, 02139, USA.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Boston, MA, 02215, USA. gordon_freeman@dfci.harvard.edu.

Abstract

Targeting immune checkpoint pathways, such as programmed death ligand-1 (PD-L1, also known as CD274 or B7-H1) or its receptor programmed cell death-1 (PD-1) has shown improved survival for patients with numerous types of cancers, not limited to lung cancer, melanoma, renal cell carcinoma, and Hodgkin lymphoma. PD-L1 is a co-inhibitory molecule whose expression on the surface of tumor cells is associated with worse prognosis in many tumors. Here we describe a splice variant (secPD-L1) that does not splice into the transmembrane domain, but instead produces a secreted form of PD-L1 that has a unique 18 amino acid tail containing a cysteine that allows it to homodimerize and more effectively inhibit lymphocyte function than monomeric soluble PD-L1. We show that recombinant secPD-L1 can dimerize and inhibit T-cell proliferation and IFN-gamma production in vitro. The secPD-L1 variant is expressed by malignant cells in vitro that also express high levels of full-length PD-L1. Transcriptomic analysis of gene expression across The Cancer Genome Atlas found the strongest association of secPD-L1 with full-length PD-L1, but also with subsets of immunologic genes, such as in myeloid-derived suppressor cells. Moreover, the splice variant is also expressed in normal tissues and within normal peripheral blood cells it is preferentially expressed in activated myeloid cells. This is the first report of a form of secreted PD-L1 that homodimerizes and is functionally active. SecPD-L1 may function as a paracrine negative immune regulator within the tumor, since secPD-L1 does not require a cell-to-cell interaction to mediate its inhibitory effect.

KEYWORDS:

Immune checkpoint; Isoforms; PD-L1; Splice variants

PMID:
30564891
PMCID:
PMC6426808
DOI:
10.1007/s00262-018-2282-1
[Indexed for MEDLINE]
Free PMC Article

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