Related Experiment Video
Updated: Jul 25, 2026
Generation of Orthotopic Pancreatic Tumors and Ex vivo Characterization of Tumor-Infiltrating T Cell Cytotoxicity
Published on: December 7, 2019
Distinct Tumor Infiltrating Immune Cell Profiles in Mice by Non-Steroidal Anti-Inflammatory Drugs (Aspirin and
Munendra Singh Tomar1, Komal Raina1,2, Neha Mishra1
1Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Abstract:
Our previous preclinical studies demonstrated that non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and naproxen significantly inhibited prostate tumorigenesis in a TMPRSS2-ERG fusion-driven model compared to non-fusion models. Since TMPRSS2-ERG fusion-positive tumors display heightened inflammatory signaling and substantial immune infiltration, we hypothesized that the differential efficacy of NSAIDs may arise from their ability to remodel the tumor immune microenvironment. Accordingly, in the present study, we systematically profiled innate and adaptive immune-cell populations: F4/80⁺ macrophages, mast cells, neutrophils, CD3⁺ T cells, CD8⁺ cytotoxic T cells, FoxP3⁺ regulatory T cells, CD20⁺ B cells, IgKC⁺ plasma cells, and Granzyme B⁺ effector cells in highly infiltrated dorso-lateral prostate regions of TMPRSS2-ERG fusion-driven and non-fusion PCa models, with and without NSAID intervention. Our analyses revealed pronounced macrophage infiltration in TMPRSS2-ERG. Ptenflox/flox and Hi-Myc+/ - model, which was further augmented by NSAIDs. Importantly, NSAID intervention shifted macrophage polarization toward an M1-like, pro-inflammatory state, contrasting with the M2-dominant phenotype characteristic of untreated tumors. NSAID treatment reduced mast cell density within the stromal compartment, suggesting suppression of mast cell-mediated tumor-promoting signals. In the fusion model, infiltration of total T cells and CD8⁺ cytotoxic T cells decreased following NSAID exposure, whereas FoxP3⁺ Tregs remained largely unaffected. Both models showed increased B-cell infiltration independent of NSAID efficacy, and no clear correlation was observed between plasma-cell presence and treatment response. Collectively, our findings offer new insight into NSAID-mediated immunomodulation in TMPRSS2-ERG fusion-driven PCa; however, further in-depth immune subtyping and spatial mapping could fully delineate the immunological mechanisms driving NSAID responsiveness.
Insights
Non-steroidal anti-inflammatory drugs (NSAIDs) show differential efficacy in prostate cancer models by remodeling the tumor immune microenvironment. NSAIDs promote pro-inflammatory macrophages and reduce mast cells, impacting cancer progression.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Prostate cancer (PCa) exhibits diverse subtypes, including TMPRSS2-ERG fusion-positive tumors with heightened inflammation.
- Non-steroidal anti-inflammatory drugs (NSAIDs) demonstrate differential efficacy in inhibiting prostate tumorigenesis, particularly in fusion-driven models.
- The tumor immune microenvironment is implicated in NSAID responsiveness.
Purpose of the Study:
- To investigate the immunomodulatory effects of NSAIDs on the tumor immune microenvironment in TMPRSS2-ERG fusion-driven and non-fusion prostate cancer models.
- To identify specific immune cell populations affected by NSAID intervention and their correlation with treatment response.
Main Methods:
- Systematic profiling of innate and adaptive immune cells (macrophages, mast cells, neutrophils, T cells, B cells, plasma cells) in prostate tumor tissues.
- Comparison of immune cell infiltration and polarization in fusion-positive and non-fusion PCa models with and without NSAID treatment.
- Analysis of macrophage polarization (M1/M2 phenotype) and T-cell subsets (CD8+, FoxP3+ Tregs).
Main Results:
- Pronounced macrophage infiltration was observed in TMPRSS2-ERG models, further augmented by NSAIDs.
- NSAID intervention shifted macrophage polarization towards a pro-inflammatory M1-like state.
- NSAID treatment reduced mast cell density and decreased CD8+ cytotoxic T cell infiltration in the fusion model.
- B-cell infiltration increased in both models, independent of NSAID efficacy.
Conclusions:
- NSAIDs modulate the tumor immune microenvironment in prostate cancer, particularly in TMPRSS2-ERG fusion-driven models.
- NSAID-induced immunomodulation involves promoting pro-inflammatory macrophages and reducing mast cells.
- Further research into immune subtyping and spatial mapping is needed to fully elucidate NSAID responsiveness mechanisms.
