American Association for Cancer Research
ccr-23-1421_supplementary_fig_11_suppsf11.pdf (7.62 MB)

Supplementary Fig 11 from KRT17high/CXCL8+ Tumor Cells Display Both Classical and Basal Features and Regulate Myeloid Infiltration in the Pancreatic Cancer Microenvironment

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posted on 2024-06-03, 07:21 authored by Eileen S. Carpenter, Padma Kadiyala, Ahmed M. Elhossiny, Samantha B. Kemp, Jay Li, Nina G. Steele, Rémy Nicolle, Zeribe C. Nwosu, Julia Freeman, Henry Dai, Daniel Paglia, Wenting Du, Katelyn Donahue, Jacqueline Morales, Paola I. Medina-Cabrera, Monica E. Bonilla, Lindsey Harris, Stephanie The, Valerie Gunchick, Nicole Peterson, Kristee Brown, Michael Mattea, Carlos E. Espinoza, Jake McGue, Sarah M. Kabala, Rachel K. Baliira, Nur M. Renollet, Ayden G. Mooney, Jianhua Liu, Sean Bhalla, Jeremy P. Farida, Christopher Ko, Jorge D. Machicado, Richard S. Kwon, Erik-Jan Wamsteker, Allison Schulman, Michelle A. Anderson, Ryan Law, Anoop Prabhu, Pierre A. Coulombe, Arvind Rao, Timothy L. Frankel, Filip Bednar, Jiaqi Shi, Vaibhav Sahai, Marina Pasca Di Magliano

CXCL8 levels in patient plasma correlate with abundance of KRT17high; CXCL8+ cancer cells in treatment naïve patients.


National Cancer Institute (NCI)

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U.S. Department of Veterans Affairs (VA)

Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM)

National Institute of Biomedical Imaging and Bioengineering (NIBIB)

United States Department of Health and Human Services

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National Institute of Allergy and Infectious Diseases (NIAID)

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Pancreatic ductal adenocarcinoma (PDAC) is generally divided in two subtypes, classical and basal. Recently, single-cell RNA sequencing has uncovered the coexistence of basal and classical cancer cells, as well as intermediary cancer cells, in individual tumors. The latter remains poorly understood; here, we sought to characterize them using a multimodal approach. We performed subtyping on a single-cell RNA sequencing dataset containing 18 human PDAC samples to identify multiple intermediary subtypes. We generated patient-derived PDAC organoids for functional studies. We compared single-cell profiling of matched blood and tumor samples to measure changes in the local and systemic immune microenvironment. We then leveraged longitudinally patient-matched blood to follow individual patients over the course of chemotherapy. We identified a cluster of KRT17-high intermediary cancer cells that uniquely express high levels of CXCL8 and other cytokines. The proportion of KRT17high/CXCL8+ cells in patient tumors correlated with intratumoral myeloid abundance, and, interestingly, high protumor peripheral blood granulocytes, implicating local and systemic roles. Patient-derived organoids maintained KRT17high/CXCL8+ cells and induced myeloid cell migration in a CXCL8-dependent manner. In our longitudinal studies, plasma CXCL8 decreased following chemotherapy in responsive patients, while CXCL8 persistence portended worse prognosis. Through single-cell analysis of PDAC samples, we identified KRT17high/CXCL8+ cancer cells as an intermediary subtype, marked by a unique cytokine profile and capable of influencing myeloid cells in the tumor microenvironment and systemically. The abundance of this cell population should be considered for patient stratification in precision immunotherapy.See related commentary by Faraoni and McAllister, p. 2297

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