FAK promotes stromal PD-L2 expression associated with poor survival in pancreatic cancer

Davidson, Catherine; Taggart, David; Sims, Andrew H.; Lonergan, David W; Canel, Marta; Serrels, Alan

doi:10.1038/s41416-022-01966-5

Cited by 14 publications

(4 citation statements)

References 64 publications

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“…By evaluating the association between pdcd1lg2 and OS or PFS, we found that high pdcd1lg2 expression was closely related to the deteriorated outcomes in BLCA, COAD, KIRP, LAML, LGG, MESO, PAAD, THCA, THYM, and UVM. These results are consistent with previous studies in bladder cancer ( 41 ), acute myeloid leukemia ( 42 ), and pancreatic ductal adenocarcinoma ( 43 , 44 ). However, some studies revealed different conclusions.…”

Section: Discussionsupporting

confidence: 93%

Pan-cancer analysis identifies PD-L2 as a tumor promotor in the tumor microenvironment

Jiang

Yuan

et al. 2023

Front. Immunol.

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BackgroundProgrammed cell death protein 1 (PD-1) receptor has two ligands,programmed death-ligand 1 (PD-L1) and PD-L2. When compared with PD-L1, PD-L2 has not received much attention, and its role remains unclear.MethodsThe expression profiles of pdcd1lg2 (PD-L2-encoding gene) mRNA and PD-L2 protein were analyzed using TCGA, ICGC, and HPA databases. Kaplan-Meier and Cox regression analyses were used to assess the prognostic significance of PD-L2. We used GSEA, Spearman’s correlation analysis and PPI network to explore the biological functions of PD-L2. PD-L2-associated immune cell infiltration was evaluated using the ESTIMATE algorithm and TIMER 2.0. The expressions of PD-L2 in tumor-associated macrophages (TAMs) in human colon cancer samples, and in mice in an immunocompetent syngeneic setting were verified using scRNA-seq datasets, multiplex immunofluorescence staining, and flow cytometry. After fluorescence-activated cell sorting, flow cytometry and qRT-PCR and transwell and colony formation assays were used to evaluate the phenotype and functions of PD-L2+TAMs. Immune checkpoint inhibitors (ICIs) therapy prediction analysis was performed using TIDE and TISMO. Last, a series of targeted small-molecule drugs with promising therapeutic effects were predicted using the GSCA platform.ResultsPD-L2 was expressed in all the common human cancer types and deteriorated outcomes in multiple cancers. PPI network and Spearman’s correlation analysis revealed that PD-L2 was closely associated with many immune molecules. Moreover, both GSEA results of KEGG pathways and GSEA results for Reactome analysis indicated that PD-L2 expression played an important role in cancer immune response. Further analysis showed that PD-L2 expression was strongly associated with the infiltration of immune cells in tumor tissue in almost all cancer types, among which macrophages were the most positively associated with PD-L2 in colon cancer. According to the results mentioned above, we verified the expression of PD-L2 in TAMs in colon cancer and found that PD-L2+TAMs population was not static. Additionally, PD-L2+TAMs exhibited protumor M2 phenotype and increased the migration, invasion, and proliferative capacity of colon cancer cells. Furthermore, PD-L2 had a substantial predictive value for ICIs therapy cohorts.ConclusionPD-L2 in the TME, especially expressed on TAMs, could be applied as a potential therapeutic target.

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Section: Discussionsupporting

confidence: 93%

Pan-cancer analysis identifies PD-L2 as a tumor promotor in the tumor microenvironment

Jiang

Yuan

et al. 2023

Front. Immunol.

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“…To investigate whether FAK expression had any impact on the cancer cell response to IFNγ, we treated FAK-wt and FAK-/- cells in vitro with 10 ng/mL IFNγ and measured (1) the secretion of chemokines and cytokines, and (2) the expression of 770 immune-related genes. Forward-phase array profiling of tumour cell-secreted proteins identified a number of IFNγ-induced chemokines and cytokines likely to mediate paracrine signalling with the TME, several of which were downregulated in response to FAK loss and are protumourigenic, such as interleukin-6 (IL-6), 25 26 in the context of pancreatic cancer ( online supplemental figure 1A ). We performed NanoString nCounter digital gene expression analysis using the PanCancer Immune Profiling Panel, which identified subsets of IFNγ-induced genes that were upregulated in FAK-/- cells compared with FAK-wt cells ( figure 1E and online supplemental table 1 ).…”

Section: Resultsmentioning

confidence: 99%

FAK suppresses antigen processing and presentation to promote immune evasion in pancreatic cancer

Canel

Sławińska

Lonergan

et al. 2023

Gut

Self Cite

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ObjectiveImmunotherapy for the treatment of pancreatic ductal adenocarcinoma (PDAC) has shown limited efficacy. Poor CD8 T-cell infiltration, low neoantigen load and a highly immunosuppressive tumour microenvironment contribute to this lack of response. Here, we aimed to further investigate the immunoregulatory function of focal adhesion kinase (FAK) in PDAC, with specific emphasis on regulation of the type-II interferon response that is critical in promoting T-cell tumour recognition and effective immunosurveillance.DesignWe combined CRISPR, proteogenomics and transcriptomics with mechanistic experiments using a KrasG12Dp53R172Hmouse model of pancreatic cancer and validated findings using proteomic analysis of human patient-derived PDAC cell lines and analysis of publicly available human PDAC transcriptomics datasets.ResultsLoss of PDAC cell-intrinsic FAK signalling promotes expression of the immunoproteasome and Major Histocompatibility Complex class-I (MHC-I), resulting in increased antigen diversity and antigen presentation by FAK-/- PDAC cells. Regulation of the immunoproteasome by FAK is a critical determinant of this response, optimising the physicochemical properties of the peptide repertoire for high affinity binding to MHC-I. Expression of these pathways can be further amplified in a STAT1-dependent manner via co-depletion of FAK and STAT3, resulting in extensive infiltration of tumour-reactive CD8 T-cells and further restraint of tumour growth. FAK-dependent regulation of antigen processing and presentation is conserved between mouse and human PDAC, but is lost in cells/tumours with an extreme squamous phenotype.ConclusionTherapies aimed at FAK degradation may unlock additional therapeutic benefit for the treatment of PDAC through increasing antigen diversity and promoting antigen presentation.

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“…30,31 The up-sPD-L2 profile observed in those post-COVID-ILD patients with lung structural and functional alterations could affect other cell subsets; reports indicated that high expression of PD-L2 is related to the presence of a macrophage subpopulation with anti-inflammatory and profibrotic functions called M2, which leads to the inhibition of T-cells, and in tumor models has been described that high expression of PD-L2 is associated with a poor prognosis. 32,33 Several studies suggest that M2 macrophages play a central role in the pathogenesis of fibrosis; for instance, M2 secretes connective tissue growth factors to mediate the proliferation and migration of fibroblasts. 34 Similarly, the depletion of the gen Mbd2 attenuates the TGF-β1 production and reduces M2 macrophage accumulation in lung fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Persistence of lung structural and functional alterations at one year post‐COVID‐19 is associated with increased serum PD‐L2 levels and altered CD4/CD8 ratio

Buendia‐Roldan,

Martínez‐Espinosa,

Aguirre

et al. 2024

Immunity Inflam & Disease

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BackgroundPersistent respiratory symptoms and lung abnormalities post‐COVID‐19 are public health problems. This study evaluated biomarkers to stratify high‐risk patients to the development or persistence of post‐COVID‐19 interstitial lung disease.MethodsOne hundred eighteen patients discharged with residual lung abnormalities compatible with interstitial lung disease (COVID‐ILD patients) after a severe COVID‐19 were followed for 1 year (post‐COVID‐ILD patients). Physical examination, pulmonary function tests, and chest high‐resolution computed tomography (HRCT) were performed. Soluble forms (s) of PD‐L1, PD‐L2, TIM‐3, and GAL‐9 were evaluated in serum and cell culture supernatant, as well as T‐cells subsets and the transmembrane expression of PD‐L1 and PD‐L2 on the cell surface.ResultsEighty percent of the post‐COVID‐ILD patients normalized their lung function at 1‐year follow‐up, 8% presented COVID‐independent ILD, and 12% still showed functional and HRCT alterations. PD‐L2 levels were heterogeneous during acute COVID‐19 (aCOVID); patients who increased (at least 30%) their sPD‐L2 levels at 1 year post‐COVID‐19 and exhibited altered CD4/CD8 ratio showed persistence of chest tomographic and functional alterations. By contrast, patients who decreased sPD‐L2 displayed a complete lung recovery. sPD‐L1, sTIM‐3, and sGAL‐9 increased significantly during aCOVID and decreased in all patients after 1‐year follow‐up.ConclusionIncreased sPD‐L2 and an altered CD4/CD8 ratio after 12 months of aCOVID are associated with the persistence of lung lesions, suggesting that they may contribute to lung damage post‐COVID‐19.

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FAK promotes stromal PD-L2 expression associated with poor survival in pancreatic cancer

Cited by 14 publications

References 64 publications

Pan-cancer analysis identifies PD-L2 as a tumor promotor in the tumor microenvironment

Pan-cancer analysis identifies PD-L2 as a tumor promotor in the tumor microenvironment

FAK suppresses antigen processing and presentation to promote immune evasion in pancreatic cancer

Persistence of lung structural and functional alterations at one year post‐COVID‐19 is associated with increased serum PD‐L2 levels and altered CD4/CD8 ratio

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