Table 1∣.

Programmed death ligand 1 signal outcomes and mechanisms

Cancer cell PDL1 signal	Subcellular PDL1 location	Functional consequence	Mechanisms	Tumour types	Experimental models and context
Intrinsic	Surface	Increase myeloid-derived suppressor cell recruitment and anti-PD1 resistance	CD8+T cell IFNγ induces cancer cell PDL1 signalling to promote STAT3-dependent, cell-intrinsic NLRP3 inflammasome activation	Melanoma	In vivo mouse models28
Intrinsic	Unknown, but localized to carboxy-terminal tail (RMLDVEKC motif)	Inhibits STAT3 activation	Inhibits IFNα, 1FNβ and IFNγ signals and sensitivity in mouse cells	Melanoma	In vitro studies of mouse cell lines27
Intrinsic	Surface	Anti-PDL1 antibodies sensitized mouse B16 melanoma cells directly to IFNβ-mediated cytotoxicity in vitro	Unknown	Melanoma, colon, breast	In vitro studies of mouse cell lines27
Intrinsic	Surface	PDL1 suppresses FAS-mediated apoptosis	Unknown but involves PD1-induced, tumour surface PDL1 back-signalling	P815 mastocytoma	In vitro studies of mouse cell lines29
Intrinsic	Surface	Promote SNAIL protein stability and immune-independent metastasis	Antagonize PTP1B, promote MAPK signalling	Breast	In vitro and in vivo human79 and mouse79 models
Intrinsic	Intracellular/perinuclear	Increase tumour resistance to chemotherapy	Enhance DNA-PK-mediated RAS–MAPK activation	Breast	In vitro studies of human cell lines81
Intrinsic	Surface	Increase tumour susceptibility to chemotherapy	Promote expression of pro-apoptotic proteins BIM and BIK	Colon (BRAFV600E)	In vitro and in vivo human25 and mouse25
Intrinsic	Nuclear	Anti-PD1 resistance	Potentially by mediating transcription of immune checkpoint ligands (e.g. VISTA, galectin 9)	Heterotopic colon cancer	In vivo mouse model36
Intrinsic	Nuclear	Possibly regulate tumour immunogenicity through hypoxia-mediated pyroptosis	Activate gasdermin C to induce tumour necrosis and tumour growth promoting inflammation	Breast	In vitro studies with human35 cell lines and in vivo mouse models35
Intrinsic	Nuclear	Increase cell proliferation by enhancing GAS6–MERTK signalling	Nuclear PDL1 binds to SP1 transcription factor to increase Gas6 gene transcription	Non-small-cell lung cancer	In vitro and in vivo studies of human cell lines80
Intrinsic	Unknown	Renders tumour immune cytolytic-resistant	Unknown, related to anti-apoptosis?	Melanoma	In vitro experiments of a syngeneic mouse cell line28
Intrinsic	Unknown	Regulates MHC class I expression possibly affecting antigen presentation	Controls transcription of immune response genes	Breast	In vitro studies of human cell lines36,91
Intrinsic	Cytosol	Cancer cell-intrinsic PDL1 regulates expression of genes involved in the DNA damage response	Cytoplasmic PDL1 binds to specific mRNAs with a GAAGAA/U motif to outcompete the RNA exosome	Breast, colon	In vitro studies of human cell lines34
Intrinsic	Unknown	Could alter chemokines/TIL trafficking	Controls tumour NF-κB-mediated transcription (e.g. binds to RelA)	Breast, colon	In vitro studies of mouse91 and human36 cell lines
Intrinsic	Unknown	Alter autophagic flux and response to autophagy inhibitors	Could affect antigen processing	Melanoma, bladder	In vitro studies of mouse23,24 and human23,24 cell lines
Intrinsic	Unknown	Promote tumour stemness	mTORC1-driven Oct4 gene expression	Melanoma, ovarian	In vitro and in vivo studies of mouse cell lines133
Intrinsic	Unknown	Increase tumour glucose metabolism	Possibly allow tumours to outcompete T cells for glucose, causing T cell dysfunction by driving mTORC1 activation	Sarcoma, B16 melanoma, L cells, MC38 colon	In vitro studies of a mouse cell line95
Intrinsic	Unknown	Increase tumour metastases	Reduce immunotherapy efficacy due to metastases	B16 melanoma, breast	In vivo studies of mouse24 and human85 models
Intrinsic	Nuclear	Promote genomic stability	Facilitate cohesin complex formation by binding cohesin subunit SA1	Rectal	In vitro studies of human38 cell lines
Intrinsic	Nuclear	Promote sister chromatid cohesion through amino-terminal YSR-like motif	Facilitate cohesin complex retention on chromatin	TNBC	In vitro studies of human cell lines37
Intrinsic, isoform	Unknown	Epithelial–mesenchymal transition signature	Activating PI3K–AKT signals; GSK3β-mediated phosphorylation, ubiquitination and degradation of SNAIL; RAS–ERK activation	Colorectal, glioblastoma, non-small-cell lung cancer, nasopharyngeal, oesophageal, TNBC	In vitro studies of human31,84,85,89 and rat84 models
Extrinsic	Surface	Reduce cell growth rate and possibly drive anti-PD1/PDL1-associated tumour growth	Tumour surface PDL1 engages tumour surface PD1 to suppress p-AKT and/or p-ERK activation	Non-small-cell lung cancer	In vitro and in vivo study of human72 cell lines/xenografts
Extrinsic	Surface	Increase cell growth rate and possibly explain anti-PD1/ PDL1 treatment response	Tumour surface PDL1 engages tumour surface PD1 to increase via p-S6 signals	Melanoma	In vitro and in vivo studies of mouse71 and human71 models; IHC from patient samples
Extrinsic	Surface	Inhibit PD1-expressing antitumour immune cells, especially T cells	Direct immune cell engagement with PDL1 back-signalling	Lung, ovary, colon, melanoma, mastocytoma, myeloma, non-small-cell lung cancer, renal cell, pancreatic, gastric, breast and non-tumour models	In vitro and in vivo human and mouse models3-12,14,15
Extrinsic	Surface	Prevent T cell co-stimulation	Interacting with CD80 in cis or in trans	Non-tumour models	In vivo mouse models51,52
Extrinsic	Surface	Induce T cell anergy, exhaustion and/or death	Direct immune cell engagement with back-signalling	Non-tumour models	In vivo human and mouse studies68,134,135
Extrinsic	Surface	Inhibit T cell memory	Reduce effector memory, T cell stem cell and resident T cell memory through unclear mechanisms	Melanoma, non-small-cell lung cancer	In vivo human136 and mouse136 studies

BIK, BCL-2-interacting killer; BIM, BCL-2-like protein 11; DNA-PK, DNA-dependent protein kinase; ERK, extracellular-signal-related kinase; IFNγ, interferon-γ; GSK3β, glutathione synthase kinase 3β; IHC, immunohistochemistry; MAPK, mitogen-activated protein kinase; MERTK, tyrosine-protein kinase MER; MHC, major histocompatibility complex; mTORC1, mammalian target of rapamycin complex 1; NF-κB, nuclear factor-κB; NLRP3, NOD-, LRR- and pyrin domain-containing 3; PD1, programmed death 1; PDL1, programmed death ligand 1; p-S6, phospho-S6 ribosomal protein; PTP1B, protein-tyrosine phosphatase 1B; RelA, REL-associated protein; SA1, cohesion subunit SA1; SP1, specificity protein 1; STAT3, signal transducer and activator of transcription 3; TIL, tumour infiltrating lymphocyte; TNBC, triple-negative breast cancer; VISTA, V-type immunoglobulin domain-containing suppressor of T cell activation.