TY - JOUR
T1 - Multimodal mapping of the tumor and peripheral blood immune landscape in human pancreatic cancer
AU - Steele, Nina G.
AU - Carpenter, Eileen S.
AU - Kemp, Samantha B.
AU - Sirihorachai, Veerin R.
AU - The, Stephanie
AU - Delrosario, Lawrence
AU - Lazarus, Jenny
AU - Amir, El ad David
AU - Gunchick, Valerie
AU - Espinoza, Carlos
AU - Bell, Samantha
AU - Harris, Lindsey
AU - Lima, Fatima
AU - Irizarry-Negron, Valerie
AU - Paglia, Daniel
AU - Macchia, Justin
AU - Chu, Angel Ka Yan
AU - Schofield, Heather
AU - Wamsteker, Erik Jan
AU - Kwon, Richard
AU - Schulman, Allison
AU - Prabhu, Anoop
AU - Law, Ryan
AU - Sondhi, Arjun
AU - Yu, Jessica
AU - Patel, Arpan
AU - Donahue, Katelyn
AU - Nathan, Hari
AU - Cho, Clifford
AU - Anderson, Michelle A.
AU - Sahai, Vaibhav
AU - Lyssiotis, Costas A.
AU - Zou, Weiping
AU - Allen, Benjamin L.
AU - Rao, Arvind
AU - Crawford, Howard C.
AU - Bednar, Filip
AU - Frankel, Timothy L.
AU - Pasca di Magliano, Marina
N1 - Funding Information:
We thank M. Cochran and T. Wightman at the Flow Cytometry Core at the University of Rochester Medical Center and A. M. Gunawan at the Indiana University Simon Cancer Center Flow Cytometry for support with cell CyTOF acquisition. We thank V. Motta and K. Brown from Fluidigm for assistance with panel design. We thank P. Schnepp and A. Ahmed for assistance with CyTOF experimental design. We thank T. Tamsen and J. Opp from the University of Michigan Advanced Genomics Core. We thank D. Hill and M. Czerwinski for input on designing single-cell analysis pipelines. We thank A. Gilado and I. Amit for expertise in building our pancreatic interactome network. We thank the Tissue Procurement Center at the University of Michigan. We thank E. Stack (formerly with PerkinElmer) for assistance with initial R introduction and basic training using inForm 2.3.0 and earlier versions and staining strategies. We thank P. Turncliff for excellent graphics. We thank J. Spence for the VE-cadherin antibody gift. This project was supported by NIH/NCI grants R01CA151588, R01CA198074 and the American Cancer Society (to M.P.d.M.). This work was also supported by a University of Michigan Cancer Center Support Grant (P30CA046592), including an administrative supplement and by NIH/NCI grant U01CA224145 H.C.C. and M.P.d.M. F.B. was funded by the Association for Academic Surgery Joel J. Roslyn Award. T.L.F. was funded by K08CA201581. S.B.K. was supported by T32-GM113900. N.G.S., V.R.S. and K.D. were supported by T32-CA009676. E.S.C. is supported by the American College of Gastroenterology Clinical Research Award and by T32-DK094775. N.G.S. is a recipient of the American Cancer Society Postdoctoral Award PF-19-096-01 and the Michigan Institute for Clinical and Health Research (MICHR) Postdoctoral Translational Scholars Program fellowship award. A.R. and S.T. were supported by institutional startup funds from the University of Michigan, a gift from Agilent Technologies, NCI grant R37CA214955 and a Research Scholar Grant from the American Cancer Society (RSG-16-005−01). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/11
Y1 - 2020/11
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85093979584&partnerID=8YFLogxK
U2 - 10.1038/s43018-020-00121-4
DO - 10.1038/s43018-020-00121-4
M3 - Article
C2 - 34296197
AN - SCOPUS:85093979584
SN - 2662-1347
VL - 1
SP - 1097
EP - 1112
JO - Nature Cancer
JF - Nature Cancer
IS - 11
ER -