Related Experiment Video
Updated: Jul 3, 2026
Artificial Antigen Presenting Cell (aAPC) Mediated Activation and Expansion of Natural Killer T Cells
Published on: December 29, 2012
ENPP3 CAR T cells combined with CD206 modulation suppress adrenocortical carcinoma
Reona Okada1, Arnulfo Mendoza1, Darryl Nousome2,3
1Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
Background:
Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with poor prognosis and limited curative treatment options. While chimeric antigen receptor (CAR) T cells have shown some promise in solid tumors, ACC remains largely unexplored in this context. Here, we used patient-derived xenograft (PDX) models of ACC to identify immunotherapeutic targets and develop novel CAR T-cell strategies.
Methods:
Target identification and tumor microenvironment (TME) profiling were conducted using publicly available bulk and single-cell RNA sequencing data from patients with ACC samples. Surface proteomic analysis and flow cytometry of PDXs were conducted to validate antigen candidates. CAR T cells were engineered and tested for cytotoxicity in vitro and in vivo and profiled using flow cytometry and cytokine analysis.
Results:
We identified ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3) as a shared immunotherapy target in 4/7 (57%) ACC PDXs. ENPP3-targeted CAR T-cells eradicated >85% of ENPP3+ ACC cells in vitro but showed attenuated efficacy in PDX mouse models. Restrained ENPP3 CAR T-cell activity correlated with immunosuppressive features of the TME, particularly the presence of CD206+ tumor-associated macrophages (TAMs). Co-treatment with an agent modulating CD206+ TAMs restored CAR T-cell function and improved antitumor responses in ENPP3high and ENPP3low PDX models (difference between mean tumor weights -270.1 mg±117.4; p<0.05).
Conclusion:
ENPP3 is a novel target for CAR T-cell therapy in ACC. ENPP3 CAR T cells, when combined with CD206 modulation to overcome immune suppression within the TME, have therapeutic efficacy in ACC by mediating robust tumor growth suppression. This combinatorial strategy, which includes CAR T cells alongside therapies that recalibrate immunosuppressive CD206+ TAMs, may be a novel approach for improved immunotherapy of solid cancers beyond ACC.
Insights
Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3) is a novel target for chimeric antigen receptor (CAR) T-cell therapy in adrenocortical carcinoma (ACC). Combining ENPP3 CAR T cells with CD206 modulation overcomes tumor microenvironment suppression for robust tumor growth control.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Biology
Background:
- Adrenocortical carcinoma (ACC) is a rare, aggressive cancer with limited treatment options.
- Chimeric antigen receptor (CAR) T-cell therapy shows potential in solid tumors but is underexplored in ACC.
Purpose of the Study:
- Identify novel immunotherapy targets for ACC.
- Develop and evaluate novel CAR T-cell strategies for ACC treatment.
Main Methods:
- Utilized RNA sequencing and proteomic analysis for target identification in ACC patient-derived xenograft (PDX) models.
- Engineered and tested ENPP3-targeted CAR T cells for efficacy in vitro and in vivo.
- Assessed the impact of tumor microenvironment components, including CD206+ tumor-associated macrophages (TAMs), on CAR T-cell function.
Main Results:
- Identified ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3) as a target in 57% of ACC PDX models.
- ENPP3-targeted CAR T cells showed significant in vitro cytotoxicity but attenuated in vivo efficacy.
- Combination therapy with CD206+ TAM modulation restored CAR T-cell function and improved antitumor responses in PDX models.
Conclusions:
- ENPP3 is a viable target for CAR T-cell therapy in ACC.
- Combining ENPP3 CAR T cells with CD206+ TAM modulation offers a promising therapeutic strategy for ACC.
- This combinatorial approach may extend to other solid cancers with immunosuppressive tumor microenvironments.
