Single-cell sequencing reveals trajectory of tumor-infiltrating lymphocyte states in pancreatic cancer
Open accessPublished version of a preprint
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has few effective treatments. Immunotherapy, an attractive alternative strategy, remains challenging with the lack of knowledge on the tumor-infiltrating lymphocyte (TIL) landscape in PDAC. To generate a reference of T-cell subpopulations, we profiled 80,000 T cells from 57 PDAC samples, 22 uninvolved/normal samples, and cultured TIL using single-cell transcriptomic and T-cell receptor analysis. These data revealed 20 cell states and heterogeneous distributions of TIL populations. The CD8+ TIL contained a putative transitional GZMK+ population based on T-cell receptor clonotype sharing, and cell-state trajectory analysis showed similarity to a GZMB+PRF1+ cytotoxic and a CXCL13+ dysfunctional population. Statistical analysis suggested that certain TIL states, such as dysfunctional and inhibitory populations, often occurred together. Finally, analysis of cultured TIL revealed that high-frequency clones from effector populations were preferentially expanded. These data provide a framework for understanding the PDAC TIL landscape for future TIL use in immunotherapy for PDAC. Significance: To improve the efficacy of immunotherapy in PDAC, there is a great need to understand the PDAC TIL landscape. This study represents a reference of PDAC TIL subpopulations and their relationships and provides a foundation upon which to base future immunotherapeutic efforts. This article is highlighted in the In This Issue feature, p. 2221
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During passaging, patient-derived organoids change their transcriptional profiles and subpopulation proportions.
“Further, patient-derived organoid transcriptional landscape and sub-population proportions shift during passaging137,271”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [271]
Single-cell RNA sequencing of PDAC cell lines and patient-derived organoids shows multiple distinct subpopulations, indicating epithelial heterogeneity persists in ex vivo models.
“In fact, PDAC cell lines and patient-derived organoid cultures demonstrate multiple, distinct, sub-populations by scRNA-seq271, highlighting epithelial cell heterogeneity even in ex vivo models.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [271]
This passaging-associated change implies that cultured organoids do not stably represent the original tumor's in vivo biology.
“suggesting that representation of the in vivo biology of the original tumor is not stable in culture.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [271]
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References 65 · Cited by 85
- Authors
- Schalck, A., Sakellariou-Thompson, D., Forget, M.-A., Sei, E., Hughes, T. G., Reuben, A., Bai, S., Hu, M., Kumar, T., Hurd, M. W., Katz, M. H. G., Tzeng, C.-W. D., Pant, S., Javle, M., Fogelman, D. R., Maitra, A., Haymaker, C. L., Kim, M. P., Navin, N. E., & Bernatchez, C.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Navin, Nicholas E.
- Bernatchez, Chantale
- ORCID
- Schalck, Aislyn
- Sakellariou-Thompson, Donastas
- Forget, Marie-Andrée
- Sei, Emi
- Hughes, Tara G.
- Reuben, Alexandre
- Bai, Shanshan
- Hu, Min
- Kumar, Tapsi
- Hurd, Mark W.
- Katz, Matthew H.G.
- Tzeng, Ching-Wei D.
- Pant, Shubham
- Javle, Milind
- Fogelman, David R.
- Maitra, Anirban
- Haymaker, Cara L.
- Kim, Michael P.
- Navin, Nicholas E.
- Bernatchez, Chantale
- Venue
- Cancer Discovery
- Published
- 2022-07-27
- Volume
- 12
- Issue
- 10
- Pages
- 2330-2349
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC9547957
- OpenAlex
- W4285727401
- Cited by
- 85
- References
- 65
- Citations by year
- 2026: 16 · 2025: 26 · 2024: 22 · 2023: 19 · 2022: 2
- FWCI
- 7.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- National Cancer Institute (RO1CA240526, RO1CA236864, K08CA218690, CA016672)
- Cancer Prevention and Research Institute of Texas (RP180684)
- National Institutes of Health (T32 CA009599)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- pancreatic ductal adenocarcinoma, tumor-infiltrating lymphocytes, T cell heterogeneity, T cell clonotypes, PRF1, CXCL13, T cell exhaustion
- MeSH terms
- Humans, Pancreatic Neoplasms, Receptors, Antigen, T-Cell, Lymphocytes, Tumor-Infiltrating, Carcinoma, Pancreatic Ductal
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