The CD155/TIGIT Axis Promotes and Maintains Immune Evasion in Neoantigen-Expressing Pancreatic Cancer

Freed-Pastor, William A.; Lambert, Laurens J.; Ely, Zackery A.; Pattada, Nimisha B.; Eng, George; Mercer, Kim L.; Patiño-García, Ana; Lin, Lin; Rideout, William M.; Hwang, William L.; Schenkel, Jason M.; Bronson, Roderick T.; Westcott, Peter M.K.; Delorey, Toni; Phillips, Devan; Yılmaz, Ömer H.; Regev, Aviv; Jacks, Tyler

doi:10.2139/ssrn.3753805

Cited by 11 publications

(14 citation statements)

References 111 publications

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“…Previous studies have found that EMT has consequences for T‐cell dysfunction and T‐cell exclusion, which induced tumour escape 40,41 . Recent findings revealed that CD155 could interact with TIGIT/CD96 on CD8 + T cells and subsequently contributed to T‐cell dysfunction 42,43 . In addition, T cells could also be excluded from the tumour site by some immunosuppressive factors in tumour microenvironment 44 .…”

Section: Discussionmentioning

confidence: 99%

“…40,41 Recent findings revealed that CD155 could interact with TIGIT/CD96 on CD8 + T cells and subsequently contributed to T-cell dysfunction. 42,43 In addition, T cells could also be excluded from the tumour site by some immunosuppressive factors in tumour microenvironment. 44 In this study, we found that high CD155 expression promoted EMT in HCC cells.…”

Section: Discussionmentioning

confidence: 99%

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CD155/SRC complex promotes hepatocellular carcinoma progression via inhibiting the p38 MAPK signalling pathway and correlates with poor prognosis

Jin

Zheng

Xian

et al. 2022

Clinical & Translational Med

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Background Hepatocellular carcinoma (HCC) is a prevalent malignancy with poor prognosis. As a cell adhesion molecule, poliovirus receptor (PVR/CD155) is abnormally overexpressed in tumour cells, and related to tumour proliferation and invasion. However, the potential role and mechanism of CD155 have not yet been elucidated in HCC. Methods Immunohistochemistry, RT‐PCR and Western blot assays were used to determine CD155 expression in HCC cell lines and tissues. Cell Counting Kit‐8 and colony formation assays were used to examine cell proliferation. Transwell and wound healing assays were used to evaluate cell migration and invasion. Cell apoptosis and cycle distribution were assessed by flow cytometry. Cox regression and Kaplan–Meier analyses were performed to explore the clinical significance of CD155. The role of CD155 in vivo was evaluated by establishing liver orthotropic xenograft mice model. RNA sequencing, bioinformatics analysis and co‐immunoprecipitation assay were used to explore the downstream signalling pathway of CD155. Results CD155 was upregulated in HCC tissues and represented a promising prognostic indicator for HCC patients ( n = 189) undergoing curative resection. High CD155 expression enhanced cell proliferation, migration and invasion, and contributed to cell survival in HCC. CD155 overexpression also induced epithelial–mesenchymal transition in HCC cells. CD155 function in HCC involved SRC/p38 MAPK signalling pathway. CD155 interacted with SRC homology‐2 domain of SRC and promoted SRC activation, further inhibiting the downstream p38 MAPK signalling pathway in HCC. Conclusions CD155 promotes HCC progression via the SRC/p38 MAPK signalling pathway. CD155 may represent a predictor for poor postsurgery prognosis in HCC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CD155/SRC complex promotes hepatocellular carcinoma progression via inhibiting the p38 MAPK signalling pathway and correlates with poor prognosis

Jin

Zheng

Xian

et al. 2022

Clinical & Translational Med

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“…Recently, Steele et al showed elevated TIGIT expression in tumor-infiltrating CD8+ T cells while PD-1 and LAG-3 were not significantly altered in human PDAC 21 . Functionally, Freed-Pastor et al used a PDAC mouse model to show that the TIGIT-PVR axis is critical for maintaining immune evasion and that TIGIT blockage elicited an immune response to PDAC 60 . TIGIT was the most expressed inhibitory checkpoint molecule on CD8+ T cells and its expression, as with other checkpoint molecules, decreased with treatment.…”

Section: Discussionmentioning

confidence: 99%

Single-Cell RNA Sequencing Reveals the Effects of Chemotherapy on Human Pancreatic Adenocarcinoma and its Tumor Microenvironment

Werba

Weissinger

Kawaler

et al. 2022

Preprint

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The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. We performed single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we found a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibited similar transcriptional responses to chemotherapy, and did not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observed decreased ligand-receptor interactions in treated samples, particularly TIGIT on CD8+ T cells and its receptor on cancer cells, and identified TIGIT as the major inhibitory checkpoint molecule of CD8+ T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.

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“…TIGIT is expressed by a subset of Tregs that suppress the activity of Th1 and Th17 cells [48,49], while in human PDAC TIGIT is expressed by Tregs and CD8+ T cells [7]. Inhibition of TIGIT combined with PD-1 blockade and CD40 activation potently induced tumor regression in orthotopic PDAC models [50]. Interestingly, TIGIT inhibition increased the production of IFN and proliferation of CD8 + T cells isolated from the blood of PDAC patients treated with FFX but did not affect the activity of CD8 + T cells isolated before the administration of FFX [51].…”

Section: Discussionmentioning

confidence: 99%

Addition of losartan to FOLFORINOX and chemoradiation downregulates pro-invasion and immunosuppression-associated genes in locally advanced pancreatic cancer

Boucher

Posada

Subudhi

et al. 2022

Preprint

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Purpose: Adding losartan to FOLFIRINOX (FFX) chemotherapy followed by chemoradiation (CRT) resulted in 61% R0 surgical resection in our phase II trial in patients with locally advanced pancreatic cancer (LAPC). Here we identify potential mechanisms of benefit by assessing the effects of neoadjuvant losartan+FFX+CRT versus FFX+CRT on the stromal tumor microenvironment. Experimental Design: We performed a gene expression analysis of RNA extracted from pancreatic cancer tissue sections and immunohistochemistry (IHC) for cancer cells and immune cells using archived surgical samples from patients treated with losartan+FFX+CRT (NCT01591733), FFX+CRT (NCT01591733) or surgery upfront, without any neoadjuvant therapy. We then assessed whether certain gene sets could stratify the overall survival (OS) of patients. Results: Neoadjuvant losartan+FFX+CRT and FFX+CRT increased the expression of genes linked to vascular normalization, transendothelial migration of leukocytes, T cell activation and cytolytic activity, and dendritic cell (DC) related genes versus no neoadjuvant treatment. In comparison to FFX+CRT, losartan+FFX+CRT downregulated pro-invasion, immunosuppression, and M2 macrophages related genes, and upregulated genes associated with tumor suppression, including the p53 pathway. Furthermore, immunostaining revealed significantly less residual disease in lesions treated with losartan+FFX+CRT versus FFX+CRT. Losartan+FFX+CRT also reduced CD4+FOXP3+ regulatory T cells in PDAC lesions with a complete/near complete response. OS was associated with DC and antigen presentation genes for patients treated with FFX+CRT, and with immunosuppression and invasion genes or DC- and blood vessel-related genes for those treated with losartan+FFX+CRT. Conclusions: Adding losartan to FFX+CRT reduced pro-invasion and immunosuppression related genes, which were associated with improved treatment outcomes in patients with LAPC.

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The CD155/TIGIT Axis Promotes and Maintains Immune Evasion in Neoantigen-Expressing Pancreatic Cancer

Cited by 11 publications

References 111 publications

CD155/SRC complex promotes hepatocellular carcinoma progression via inhibiting the p38 MAPK signalling pathway and correlates with poor prognosis

CD155/SRC complex promotes hepatocellular carcinoma progression via inhibiting the p38 MAPK signalling pathway and correlates with poor prognosis

Single-Cell RNA Sequencing Reveals the Effects of Chemotherapy on Human Pancreatic Adenocarcinoma and its Tumor Microenvironment

Addition of losartan to FOLFORINOX and chemoradiation downregulates pro-invasion and immunosuppression-associated genes in locally advanced pancreatic cancer

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