Related Experiment Video
Updated: Feb 23, 2026
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer
Fee Bengsch1,2, Dawson M Knoblock1,2, Anni Liu1,2
1Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Abstract:
The ability of some tumors to exclude effector T cells represents a major challenge to immunotherapy. T cell exclusion is particularly evident in pancreatic ductal adenocarcinoma (PDAC), a disease where blockade of the immune checkpoint molecule CTLA-4 has not produced significant clinical activity. In PDAC, effector T cells are often scarce within tumor tissue and confined to peritumoral lymph nodes and lymphoid aggregates. We hypothesized that CTLA-4 blockade, despite a lack of clinical efficacy seen thus far in PDAC, might still alter T cell immunobiology, which would have therapeutic implications. Using clinically relevant genetic models of PDAC, we found that regulatory T cells (Tregs), which constitutively express CTLA-4, accumulate early during tumor development but are largely confined to peritumoral lymph nodes during disease progression. Tregs were observed to regulate CD4+, but not CD8+, T cell infiltration into tumors through a CTLA-4/CD80 dependent mechanism. Disrupting CTLA-4 interaction with CD80 was sufficient to induce CD4 T cell infiltration into tumors. These data have important implications for T cell immunotherapy in PDAC and demonstrate a novel role for CTLA-4/CD80 interactions in regulating T cell exclusion. In addition, our findings suggest distinct mechanisms govern CD4+ and CD8+ T cell infiltration in PDAC.
Insights
Regulatory T cells (Tregs) in pancreatic cancer exclude CD4 T cells via CTLA-4/CD80 signaling. Blocking this interaction may improve T cell immunotherapy for pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Tumor-infiltrating lymphocytes (TILs) are crucial for effective cancer immunotherapy.
- Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor T cell infiltration, limiting immunotherapy efficacy.
- Immune checkpoint blockade, such as anti-CTLA-4 therapy, has shown limited success in PDAC.
Purpose of the Study:
- To investigate the role of CTLA-4 in T cell exclusion within PDAC.
- To explore the potential therapeutic implications of modulating CTLA-4 signaling in PDAC immunotherapy.
Main Methods:
- Utilized genetically engineered mouse models of PDAC.
- Analyzed the distribution and function of regulatory T cells (Tregs) and their interaction with CTLA-4 and CD80.
- Assessed the impact of disrupting CTLA-4/CD80 interactions on T cell infiltration.
Main Results:
- Regulatory T cells (Tregs), expressing CTLA-4, accumulate early in PDAC development but are primarily located in peritumoral lymph nodes.
- Tregs regulate CD4+ T cell infiltration into tumors via a CTLA-4/CD80-dependent mechanism, but not CD8+ T cells.
- Disruption of the CTLA-4/CD80 interaction successfully induced CD4+ T cell infiltration into PDAC tumors.
Conclusions:
- CTLA-4/CD80 interactions play a critical role in mediating T cell exclusion in PDAC.
- Targeting CTLA-4/CD80 interactions represents a novel strategy to enhance CD4+ T cell infiltration and potentially improve immunotherapy outcomes in PDAC.
- Distinct mechanisms govern CD4+ and CD8+ T cell infiltration in PDAC, suggesting differential therapeutic approaches.
