An Extended PD-L2 Cytoplasmic Domain Results From Alternative Splicing in NSCLC Cells

Lisa Loksø Dietz; Natasja Toft Furman; Trine Vilsbøll Larsen; Tina Fuglsang Daugaard; Emil Aagaard Thomsen; Johanne Lade Keller; Lars Aagaard; Boe Sandahl Sorensen; Anders Lade Nielsen

doi:10.1097/CJI.0000000000000439

An Extended PD-L2 Cytoplasmic Domain Results From Alternative Splicing in NSCLC Cells

Lisa Loksø Dietz, Natasja Toft Furman, Trine Vilsbøll Larsen, Tina Fuglsang Daugaard, Emil Aagaard Thomsen, Johanne Lade Keller, Lars Aagaard, Boe Sandahl Sorensen, Anders Lade Nielsen^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

6 Citations (Scopus)

Abstract

Antibody-based immunotherapy targeting the interaction between programmed cell death 1 (PD-1) and its ligand PD-L1 has shown impressive clinical outcomes in various cancer types, including nonsmall cell lung cancer (NSCLC). However, regulatory mechanisms in this immune checkpoint pathway still needs clarification. PD-L2 is structurally homologous to PD-L1 and is a second PD-1 ligand. Alternative mRNA splicing from the CD274 and PDCD1LG2 genes holds the potential to generate PD-L1 and PD-L2 isoforms, respectively, with novel functionality in regulation of the PD-1 immune checkpoint pathway. Here, we describe alternative splicing in NSCLC cells potentially generating eight different PD-L2 isoforms from the PDCD1LG2 gene. Extension of exon 6 by four nucleotides is the most prominent alternative splicing event and results in PD-L2 isoform V with a cytoplasmic domain containing a 10 amino acid extension. On average 13% of the PDCD1LG2 transcripts in NSCLC cell lines and 22% of the transcripts in NSCLC tumor biopsies encode PD-L2 isoform V. PD-L2 isoform V localizes to the cell surface membrane but less efficiently than the canonical PD-L2 isoform I. The cytoplasmic domains of PD-1 ligands can affect immune checkpoint pathways by conferring membrane localization and protein stability and thereby represent alternative targets for immunotherapy. In addition, cytoplasmic domains are involved in intracellular signalling cascades in cancer cells. The presented observations of different cytoplasmic domains of PD-L2 will be important in the future delineation of the PD-1 immune checkpoint pathway.

Original language	English
Journal	Journal of Immunotherapy
Volume	45
Issue	9
Pages (from-to)	379-388
Number of pages	10
ISSN	1524-9557
DOIs	https://doi.org/10.1097/CJI.0000000000000439
Publication status	Published - Nov 2022

Keywords

checkpoint inhibitor immunotherapy
lung cancer
molecular shield
PD-1/PD PD-L-axis

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10.1097/CJI.0000000000000439

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title = "An Extended PD-L2 Cytoplasmic Domain Results From Alternative Splicing in NSCLC Cells",

abstract = "Antibody-based immunotherapy targeting the interaction between programmed cell death 1 (PD-1) and its ligand PD-L1 has shown impressive clinical outcomes in various cancer types, including nonsmall cell lung cancer (NSCLC). However, regulatory mechanisms in this immune checkpoint pathway still needs clarification. PD-L2 is structurally homologous to PD-L1 and is a second PD-1 ligand. Alternative mRNA splicing from the CD274 and PDCD1LG2 genes holds the potential to generate PD-L1 and PD-L2 isoforms, respectively, with novel functionality in regulation of the PD-1 immune checkpoint pathway. Here, we describe alternative splicing in NSCLC cells potentially generating eight different PD-L2 isoforms from the PDCD1LG2 gene. Extension of exon 6 by four nucleotides is the most prominent alternative splicing event and results in PD-L2 isoform V with a cytoplasmic domain containing a 10 amino acid extension. On average 13% of the PDCD1LG2 transcripts in NSCLC cell lines and 22% of the transcripts in NSCLC tumor biopsies encode PD-L2 isoform V. PD-L2 isoform V localizes to the cell surface membrane but less efficiently than the canonical PD-L2 isoform I. The cytoplasmic domains of PD-1 ligands can affect immune checkpoint pathways by conferring membrane localization and protein stability and thereby represent alternative targets for immunotherapy. In addition, cytoplasmic domains are involved in intracellular signalling cascades in cancer cells. The presented observations of different cytoplasmic domains of PD-L2 will be important in the future delineation of the PD-1 immune checkpoint pathway.",

keywords = "checkpoint inhibitor immunotherapy, lung cancer, molecular shield, PD-1/PD PD-L-axis",

author = "Dietz, {Lisa Loks{\o}} and Furman, {Natasja Toft} and Larsen, {Trine Vilsb{\o}ll} and Daugaard, {Tina Fuglsang} and Thomsen, {Emil Aagaard} and Keller, {Johanne Lade} and Lars Aagaard and Sorensen, {Boe Sandahl} and Nielsen, {Anders Lade}",

year = "2022",

month = nov,

doi = "10.1097/CJI.0000000000000439",

language = "English",

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An Extended PD-L2 Cytoplasmic Domain Results From Alternative Splicing in NSCLC Cells. / Dietz, Lisa Loksø; Furman, Natasja Toft; Larsen, Trine Vilsbøll et al.
In: Journal of Immunotherapy, Vol. 45, No. 9, 11.2022, p. 379-388.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - An Extended PD-L2 Cytoplasmic Domain Results From Alternative Splicing in NSCLC Cells

AU - Dietz, Lisa Loksø

AU - Furman, Natasja Toft

AU - Larsen, Trine Vilsbøll

AU - Daugaard, Tina Fuglsang

AU - Thomsen, Emil Aagaard

AU - Keller, Johanne Lade

AU - Aagaard, Lars

AU - Sorensen, Boe Sandahl

AU - Nielsen, Anders Lade

PY - 2022/11

Y1 - 2022/11

N2 - Antibody-based immunotherapy targeting the interaction between programmed cell death 1 (PD-1) and its ligand PD-L1 has shown impressive clinical outcomes in various cancer types, including nonsmall cell lung cancer (NSCLC). However, regulatory mechanisms in this immune checkpoint pathway still needs clarification. PD-L2 is structurally homologous to PD-L1 and is a second PD-1 ligand. Alternative mRNA splicing from the CD274 and PDCD1LG2 genes holds the potential to generate PD-L1 and PD-L2 isoforms, respectively, with novel functionality in regulation of the PD-1 immune checkpoint pathway. Here, we describe alternative splicing in NSCLC cells potentially generating eight different PD-L2 isoforms from the PDCD1LG2 gene. Extension of exon 6 by four nucleotides is the most prominent alternative splicing event and results in PD-L2 isoform V with a cytoplasmic domain containing a 10 amino acid extension. On average 13% of the PDCD1LG2 transcripts in NSCLC cell lines and 22% of the transcripts in NSCLC tumor biopsies encode PD-L2 isoform V. PD-L2 isoform V localizes to the cell surface membrane but less efficiently than the canonical PD-L2 isoform I. The cytoplasmic domains of PD-1 ligands can affect immune checkpoint pathways by conferring membrane localization and protein stability and thereby represent alternative targets for immunotherapy. In addition, cytoplasmic domains are involved in intracellular signalling cascades in cancer cells. The presented observations of different cytoplasmic domains of PD-L2 will be important in the future delineation of the PD-1 immune checkpoint pathway.

AB - Antibody-based immunotherapy targeting the interaction between programmed cell death 1 (PD-1) and its ligand PD-L1 has shown impressive clinical outcomes in various cancer types, including nonsmall cell lung cancer (NSCLC). However, regulatory mechanisms in this immune checkpoint pathway still needs clarification. PD-L2 is structurally homologous to PD-L1 and is a second PD-1 ligand. Alternative mRNA splicing from the CD274 and PDCD1LG2 genes holds the potential to generate PD-L1 and PD-L2 isoforms, respectively, with novel functionality in regulation of the PD-1 immune checkpoint pathway. Here, we describe alternative splicing in NSCLC cells potentially generating eight different PD-L2 isoforms from the PDCD1LG2 gene. Extension of exon 6 by four nucleotides is the most prominent alternative splicing event and results in PD-L2 isoform V with a cytoplasmic domain containing a 10 amino acid extension. On average 13% of the PDCD1LG2 transcripts in NSCLC cell lines and 22% of the transcripts in NSCLC tumor biopsies encode PD-L2 isoform V. PD-L2 isoform V localizes to the cell surface membrane but less efficiently than the canonical PD-L2 isoform I. The cytoplasmic domains of PD-1 ligands can affect immune checkpoint pathways by conferring membrane localization and protein stability and thereby represent alternative targets for immunotherapy. In addition, cytoplasmic domains are involved in intracellular signalling cascades in cancer cells. The presented observations of different cytoplasmic domains of PD-L2 will be important in the future delineation of the PD-1 immune checkpoint pathway.

KW - checkpoint inhibitor immunotherapy

KW - lung cancer

KW - molecular shield

KW - PD-1/PD PD-L-axis

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DO - 10.1097/CJI.0000000000000439

M3 - Journal article

C2 - 36036966

AN - SCOPUS:85139471561

SN - 1524-9557

VL - 45

SP - 379

EP - 388

JO - Journal of Immunotherapy

JF - Journal of Immunotherapy

IS - 9

ER -

An Extended PD-L2 Cytoplasmic Domain Results From Alternative Splicing in NSCLC Cells

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