Abstract PO-046: Dissecting the role of tumor-intrinsic Cxcl1 in mediating immune exclusion in Ras-p53 cooperative pancreatic cancer
| العنوان: | Abstract PO-046: Dissecting the role of tumor-intrinsic Cxcl1 in mediating immune exclusion in Ras-p53 cooperative pancreatic cancer |
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| المؤلفون: | Antonio Colaprico, Jashodeep Datta, Siddharth Mehra, Anna Bianchi, Iago De Castro Silva, Samara Singh, Prateek Sharma, Daisy Dai, Nagaraj S. Nagathihalli, Austin R. Dosch, Nipun B. Merchant |
| المصدر: | Cancer Research. 80:PO-046 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Cancer Research, Tumor microenvironment, Myeloid, CD33, Cancer, Biology, medicine.disease, Immunophenotyping, medicine.anatomical_structure, Immune system, Oncology, Pancreatic cancer, medicine, Cancer research, CD8 |
| الوصف: | INTRODUCTION: Ras-p53 cooperative mutations, which define >50% of human pancreatic ductal adenocarcinoma (PDAC), promote an immune-excluded tumor microenvironment. In Ras-p53 murine models that phenocopy human PDAC, overexpression of the myeloid chemo-attractant Cxcl1 is associated with T-cell exclusion. We sought to dissect the role of tumor-intrinsic Cxcl1 in mediating immune exclusion in Ras-p53 PDAC. METHODS: Single-cell immune deconvolution and Cxcl1 expression were queried in TCGA PDAC samples (n=150). Single-cell RNA sequencing (scRNAseq) data in KrasG12D/+;Trp53fl/+;Pdx1Cre (KPC WT) genetically engineered mice (GEM) were interrogated. CRISPR/Cas9-based genome editing was used to silence Cxcl1 in KPC tumor cells (KPC-Cxcl1KO). Multiparameter flow cytometry-based immunophenotyping of tumor-infiltrating and circulating myeloid/T-cell populations was performed in in-vivo orthotopic models utilizing KPCWT / KPC-Cxcl1KO cells. RESULTS: In human TCGA samples, Cxcl1 overexpression was strongly associated with expression of its cognate receptor CXCR2, reduced CD4+/CD8+ T-cells, and increased CD33+ myeloid-derived suppressor cells (MDSCs). In KPC GEMs, scRNAseq revealed that CXCR2 expression was exclusively present on the polymorphonuclear MDSC subset (PMN-MDSC). Exogenous Cxcl1 conditioning in murine bone marrow-derived cells induced PMN-MDSC polarization and upregulated CXCR2. Genetic ablation of Cxcl1 in KPC tumor cells disrupted transwell migration of splenocyte-enriched MDSC in-vitro; this effect was dependent on CXCR2 expression on MDSCs. There was a dramatic reduction in tumor weights and metastatic outgrowth (p Citation Format: Anna Bianchi, Siddharth Mehra, Daisy Dai, Iago de Castro Silva, Prateek Sharma, Antonio Colaprico, Austin R. Dosch, Samara Singh, Nagaraj S. Nagathihalli, Nipun B. Merchant, Jashodeep Datta. Dissecting the role of tumor-intrinsic Cxcl1 in mediating immune exclusion in Ras-p53 cooperative pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-046. |
| تدمد: | 1538-7445 0008-5472 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::dcd3acefb8bed5ef986e6c233277cfa7Test https://doi.org/10.1158/1538-7445.panca20-po-046Test |
| رقم الانضمام: | edsair.doi...........dcd3acefb8bed5ef986e6c233277cfa7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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