Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic Cancer.

Abstract

Pancreatic ductal adenocarcinoma (PDA) is characterized by an immune-suppressive tumor microenvironment that renders it largely refractory to immunotherapy. We implemented a multimodal analysis approach to elucidate the immune landscape in PDA. Using a combination of CyTOF, single-cell RNA sequencing, and multiplex immunohistochemistry on patient tumors, matched blood, and non-malignant samples, we uncovered a complex network of immune-suppressive cellular interactions. These experiments revealed heterogeneous expression of immune checkpoint receptors in individual patient's T cells and increased markers of CD8+ T cell dysfunction in advanced disease stage. Tumor-infiltrating CD8+ T cells had an increased proportion of cells expressing an exhausted expression profile that included upregulation of the immune checkpoint TIGIT, a finding that we validated at the protein level. Our findings point to a profound alteration of the immune landscape of tumors, and to patient-specific immune changes that should be taken into account as combination immunotherapy becomes available for pancreatic cancer.

• Authors: Nina G Steele, Eileen S Carpenter, Samantha B Kemp, Veerin R Sirihorachai, Stephanie The, Lawrence Delrosario, Jenny Lazarus, El-Ad David Amir, Valerie Gunchick, Carlos Espinoza, Samantha Bell, Lindsey Harris, Fatima Lima, Valerie Irizarry-Negron, Daniel Paglia, Justin Macchia, Angel Ka Yan Chu, Heather Schofield, Erik-Jan Wamsteker, Richard Kwon, Allison Schulman, Anoop Prabhu, Ryan Law, Arjun Sondhi, Jessica Yu, Arpan Patel, Katelyn Donahue, Hari Nathan, Clifford Cho, Michelle A Anderson, Vaibhav Sahai, Costas A Lyssiotis, Weiping Zou, Benjamin L Allen, Arvind Rao, Howard C Crawford, Filip Bednar, Timothy L Frankel, Marina Pasca di Magliano
• Journal: Nature cancer (Nat Cancer) Vol. 1 Issue 11 Pg. 1097-1112 (11 2020) ISSN: 2662-1347 [Electronic] England
• PMID: 34296197 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Topics

• CD8-Positive T-Lymphocytes (pathology)
• Humans
• Pancreatic Neoplasms (pathology)
• Tumor Microenvironment (genetics)