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Pancreatic Tissue Dissection to Isolate Viable Single Cells
Published on: May 26, 2023
scRNA-seq reveals chemotherapy-induced tumor microenvironment changes in pancreatic ductal adenocarcinoma
Fei Gao1, Yuxiong Lu2,3, Yanyan Zhao2,3
1National Institutes for Food and Drug Control, Beijing, China.
Background:
Challenges have arisen in finding an effective treatment for pancreatic ductal adenocarcinoma (PDAC). Poor outcomes have fueled ongoing efforts to exploit the tumor microenvironment (TME) in the treatment of PDAC; however, to date, treatment strategies have largely failed. Thus, a comprehensive and deep understanding of the PDAC TME is necessary. The purpose of the present study was to investigate chemotherapy-induced tumor microenvironment changes and to optimize the response to immunotherapy in PDAC.
Methods:
We analyzed publicly available single-cell RNA sequencing (scRNA-seq) PDAC (with or without standard chemotherapy) data and performed systematic analyses to elucidate novel mechanisms and to determinate the marker expression alteration induced by the chemotherapy.
Results:
Lysozyme (LYZ), which is usually used as a myeloid marker, was significantly increased in the tumor cells, including myeloid cells responding to chemotherapy. Additionally, chemotherapy altered the mechanism of antigen presentation and modulated the TME, which may lead to tumor drug resistance and recurrence. Chemotherapy also affected the receptor of polio virus receptor (PVR) signaling, which shifted from TIGIT in T cells to CD226 in myeloid cells. Thus, PVR (rather than TIGIT) should be the target for treatment.
Conclusions:
We described the characteristics of widely expressed markers in different cell types in PDAC. Chemotherapy disrupted the TME balance, altered tumor antigen presentation, and changed PVR signaling. Combining the appropriate chemical and immune therapies could improve the immune therapy response in PDAC.
Insights
Chemotherapy alters the pancreatic cancer tumor microenvironment (TME), affecting antigen presentation and PVR signaling. Targeting PVR in myeloid cells may improve immunotherapy response in pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) treatment remains challenging, with poor outcomes necessitating novel therapeutic strategies.
- Exploiting the tumor microenvironment (TME) is a key focus, but current strategies have limited success.
- A deep understanding of PDAC TME dynamics is crucial for developing effective treatments.
Purpose of the Study:
- To investigate chemotherapy-induced alterations within the pancreatic ductal adenocarcinoma tumor microenvironment.
- To identify mechanisms driving treatment resistance and recurrence.
- To optimize immunotherapy response in PDAC by understanding TME modulation.
Main Methods:
- Analysis of publicly available single-cell RNA sequencing (scRNA-seq) data from PDAC patients.
- Systematic investigation of marker expression changes induced by chemotherapy.
- Elucidation of novel molecular mechanisms underlying chemotherapy effects on the TME.
Main Results:
- Chemotherapy significantly increased Lysozyme (LYZ) expression in tumor and myeloid cells.
- Antigen presentation mechanisms were altered, potentially contributing to drug resistance and recurrence.
- Polio virus receptor (PVR) signaling shifted from TIGIT in T cells to CD226 in myeloid cells.
Conclusions:
- Chemotherapy disrupts TME balance, alters tumor antigen presentation, and modifies PVR signaling pathways in PDAC.
- PVR, particularly its interaction with CD226 in myeloid cells, represents a potential therapeutic target.
- Combination therapy with chemotherapy and immunotherapy holds promise for improving treatment outcomes in PDAC.
