Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic Cancer
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:1 |
|---|---|
| Enthalten in: |
Nature cancer - 1(2020), 11 vom: 14. Nov., Seite 1097-1112 |
| Sprache: |
Englisch |
|---|
| Links: |
|---|
| Themen: |
CD8+ T cells |
|---|
| Anmerkungen: |
Date Completed 14.04.2022 Date Revised 07.02.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s43018-020-00121-4 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM328411191 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM328411191 | ||
| 003 | DE-627 | ||
| 005 | 20240207231934.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s43018-020-00121-4 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1283.xml |
| 035 | |a (DE-627)NLM328411191 | ||
| 035 | |a (NLM)34296197 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Steele, Nina G |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic Cancer |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 14.04.2022 | ||
| 500 | |a Date Revised 07.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CD8+ T cells | |
| 650 | 4 | |a Single-cell RNA sequencing | |
| 650 | 4 | |a TIGIT | |
| 650 | 4 | |a immune checkpoints | |
| 650 | 4 | |a pancreatic cancer | |
| 650 | 4 | |a tumor immunology | |
| 700 | 1 | |a Carpenter, Eileen S |e verfasserin |4 aut | |
| 700 | 1 | |a Kemp, Samantha B |e verfasserin |4 aut | |
| 700 | 1 | |a Sirihorachai, Veerin R |e verfasserin |4 aut | |
| 700 | 1 | |a The, Stephanie |e verfasserin |4 aut | |
| 700 | 1 | |a Delrosario, Lawrence |e verfasserin |4 aut | |
| 700 | 1 | |a Lazarus, Jenny |e verfasserin |4 aut | |
| 700 | 1 | |a Amir, El-Ad David |e verfasserin |4 aut | |
| 700 | 1 | |a Gunchick, Valerie |e verfasserin |4 aut | |
| 700 | 1 | |a Espinoza, Carlos |e verfasserin |4 aut | |
| 700 | 1 | |a Bell, Samantha |e verfasserin |4 aut | |
| 700 | 1 | |a Harris, Lindsey |e verfasserin |4 aut | |
| 700 | 1 | |a Lima, Fatima |e verfasserin |4 aut | |
| 700 | 1 | |a Irizarry-Negron, Valerie |e verfasserin |4 aut | |
| 700 | 1 | |a Paglia, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Macchia, Justin |e verfasserin |4 aut | |
| 700 | 1 | |a Chu, Angel Ka Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Schofield, Heather |e verfasserin |4 aut | |
| 700 | 1 | |a Wamsteker, Erik-Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Kwon, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Schulman, Allison |e verfasserin |4 aut | |
| 700 | 1 | |a Prabhu, Anoop |e verfasserin |4 aut | |
| 700 | 1 | |a Law, Ryan |e verfasserin |4 aut | |
| 700 | 1 | |a Sondhi, Arjun |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Jessica |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Arpan |e verfasserin |4 aut | |
| 700 | 1 | |a Donahue, Katelyn |e verfasserin |4 aut | |
| 700 | 1 | |a Nathan, Hari |e verfasserin |4 aut | |
| 700 | 1 | |a Cho, Clifford |e verfasserin |4 aut | |
| 700 | 1 | |a Anderson, Michelle A |e verfasserin |4 aut | |
| 700 | 1 | |a Sahai, Vaibhav |e verfasserin |4 aut | |
| 700 | 1 | |a Lyssiotis, Costas A |e verfasserin |4 aut | |
| 700 | 1 | |a Zou, Weiping |e verfasserin |4 aut | |
| 700 | 1 | |a Allen, Benjamin L |e verfasserin |4 aut | |
| 700 | 1 | |a Rao, Arvind |e verfasserin |4 aut | |
| 700 | 1 | |a Crawford, Howard C |e verfasserin |4 aut | |
| 700 | 1 | |a Bednar, Filip |e verfasserin |4 aut | |
| 700 | 1 | |a Frankel, Timothy L |e verfasserin |4 aut | |
| 700 | 1 | |a Pasca di Magliano, Marina |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nature cancer |d 2020 |g 1(2020), 11 vom: 14. Nov., Seite 1097-1112 |w (DE-627)NLM307030067 |x 2662-1347 |7 nnns |
| 773 | 1 | 8 | |g volume:1 |g year:2020 |g number:11 |g day:14 |g month:11 |g pages:1097-1112 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s43018-020-00121-4 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 1 |j 2020 |e 11 |b 14 |c 11 |h 1097-1112 | ||