Multimodal mapping of the tumor and peripheral blood immune landscape in human pancreatic cancer (PBMC)

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

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 patients’ T cells and increased markers of CD8+ T cell dysfunction in the 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.