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Updated: Jul 15, 2025
Author Spotlight: Exploring Strategies for Successful Immune Response Against Tumors
Published on: August 16, 2024
Single-cell RNA-seq reveals characteristics in tumor microenvironment of PDAC with MSI-H following neoadjuvant
Kai Chen1, Yongsu Ma1, Xinxin Liu1
1Department of General Surgery, Peking University First Hospital, Beijing, 100034, China.
Abstract:
Accumulating evidence suggests the minority of patients with advanced pancreatic ductal adenocarcinoma (PDAC) that have microsatellite instability high (MSI-H) can benefit from immune checkpoint inhibitors (ICIs). However, the effects of ICIs on the tumor microenvironment (TME) of PDAC remain elusive. We conducted single-cell RNA-seq (scRNA-seq) analysis on a residual lesion from a MSI-H PDAC patient who received a radical operation after eight cycles of neoadjuvant treatment (nab-paclitaxel/gemcitabine plus pembrolizumab). Multiple tumor subclusters were identified in residual lesion after neoadjuvant treatment, one of which was mainly composed of cells in the S and G2M phases. This subcluster also had enriched expression of MKI67 and PCNA and cell cycle-related signatures and was thus defined as a proliferating tumor subcluster. This subcluster had higher S_score, Fatty acid_score, UPR_score, and Glycolysis_score than others. We also identified characteristics of the TME after neoadjuvant treatment by comparing the excised primary tumors form nontreated PDAC and the residual lesion. The residual lesion was characterized with activated pancreatic stellate cells (PSCs) and exhausted T cells (Tex). We compared the receptor-ligand interactions between the two groups, and found that no checkpoint receptor-ligand pairs between T cells and tumor cells were identified in the residual lesion, while there were many checkpoint receptor-ligand pairs in the nontreated primary PDAC. In conclusion, our findings revealed the characteristics of residual lesion of advanced PDAC with MSI-H upon combination treatment of chemotherapy and immunotherapy, which might provide some valuable clues for solving the puzzle of ICI in PDAC.
Insights
Immune checkpoint inhibitors (ICIs) show promise for advanced pancreatic ductal adenocarcinoma (PDAC) with high microsatellite instability (MSI-H). This study reveals TME changes, including activated PSCs and exhausted T cells, after neoadjuvant therapy in MSI-H PDAC.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Advanced pancreatic ductal adenocarcinoma (PDAC) with high microsatellite instability (MSI-H) represents a small subset of patients who may benefit from immune checkpoint inhibitors (ICIs).
- The impact of ICIs on the tumor microenvironment (TME) in PDAC remains largely unknown.
- Understanding TME dynamics is crucial for optimizing immunotherapy strategies in PDAC.
Purpose of the Study:
- To investigate the characteristics of the tumor microenvironment (TME) in advanced MSI-H PDAC following neoadjuvant chemotherapy and immunotherapy.
- To identify specific tumor subclusters and cellular interactions within the residual lesion after treatment.
- To compare the TME of treated residual lesions with untreated primary PDAC.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) was performed on a residual lesion from an MSI-H PDAC patient after neoadjuvant treatment (nab-paclitaxel/gemcitabine plus pembrolizumab).
- Tumor subclusters were identified, and their biological signatures (e.g., cell cycle, metabolic scores) were analyzed.
- Receptor-ligand interactions were compared between the residual lesion and untreated primary PDAC samples to assess TME changes.
Main Results:
- A proliferating tumor subcluster with enriched cell cycle-related signatures and higher metabolic scores (Fatty acid, UPR, Glycolysis) was identified in the residual lesion.
- The residual lesion TME was characterized by activated pancreatic stellate cells (PSCs) and exhausted T cells (Tex).
- Checkpoint receptor-ligand interactions between T cells and tumor cells were absent in the residual lesion, unlike in untreated primary PDAC.
Conclusions:
- Neoadjuvant combination therapy in advanced MSI-H PDAC leads to distinct TME alterations, including specific tumor subcluster characteristics and immune cell states.
- The reduction in checkpoint receptor-ligand pairs in the residual lesion suggests a potential mechanism for ICI efficacy or resistance.
- These findings offer insights into the TME response to combined chemo-immunotherapy in PDAC, potentially guiding future treatment strategies.
