Steele et al. used mass cytometry, single cell RNAseq, and multiplex immunohistochemistry on pancreatic tumors, non-malignant samples, and matched blood to perform in-depth immune characterization of human pancreatic ductal adenocarcinoma (PDA) and determined multiple patient-specific mechanisms of immune suppression. PDA tumors showed heterogeneous immune infiltration and immune checkpoint ligand expression. Tumor-infiltrating CD8+ T cells showed an exhausted gene expression signature with progressive dysfunction in advanced disease. Tumor-infiltrating exhausted T cells and NK cells showed increased expression of TIGIT, revealing a potential target.
Contributed by Shishir Pant
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.
Author Info: (1) Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. (2) Department of Internal Medicine, Division of Gastroenterology, University of
Author Info: (1) Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. (2) Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor MI 48109, USA. (3) Molecular and Cellular Pathology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA. (4) Cancer Biology Program, University of Michigan, Ann Arbor, MI 48109, USA. (5) Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA. (6) Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. (7) Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. (8) Astrolabe Diagnostics, Inc., Fort Lee, NJ, 07024, USA. (9) Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA. (10) Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. (11) Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. (12) Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. (13) Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. (14) Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. (15) Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. (16) Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. (17) Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA. (18) Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. (19) Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor MI 48109, USA. (20) Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor MI 48109, USA. (21) Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor MI 48109, USA. (22) Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor MI 48109, USA. (23) Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor MI 48109, USA. (24) Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor MI 48109, USA. (25) Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor MI 48109, USA. (26) Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor MI 48109, USA. (27) Cancer Biology Program, University of Michigan, Ann Arbor, MI 48109, USA. (28) Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. (29) Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. (30) Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor MI 48109, USA. (31) Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA. (32) Molecular and Cellular Pathology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA. Cancer Biology Program, University of Michigan, Ann Arbor, MI 48109, USA. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. (33) Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. (34) Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. (35) Cancer Biology Program, University of Michigan, Ann Arbor, MI 48109, USA. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA. Michigan Institute of Data Science (MIDAS), University of Michigan, Ann Arbor, MI 48109, USA. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA. (36) Molecular and Cellular Pathology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA. Cancer Biology Program, University of Michigan, Ann Arbor, MI 48109, USA. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. (37) Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. (38) Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. (39) Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Molecular and Cellular Pathology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA. Cancer Biology Program, University of Michigan, Ann Arbor, MI 48109, USA. Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
