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Peer-reviewedCC BY 4.0Cancer Research Communications

Cancer Cell CD73 Loss Promotes a Dual Inflammatory and Immunosuppressive Microenvironment in Endometrial Carcinoma

  • Hannah N. Lee1
  • Xingyuan Zhang1
  • Suzanne M. Crumley2
  • Emily M. Rabjohns1,3
  • Luan H. Phan4
  • Di Wu5,6
  • Russell R. Broaddus1,7
  • Cyrus Vaziri1,7
  • Jessica L. Bowser1,7
7 affiliations
  1. 1Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  2. 2Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
  3. 3Graduate Curriculum in Pathobiology and Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
  4. 4Department of Internal Medicine, University of Texas McGovern Medical School, Houston, Texas.
  5. 5Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
  6. 6Department of Biomedical Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
  7. 7UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
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Abstract

CD73 is an emerging immunotherapy target that is overexpressed in many tumors and generates an adenosine-rich microenvironment to suppress antitumor immunity. In low-grade endometrial carcinoma, CD73 expression varies, and its impact on tumor immunobiology is unknown. Using two microsatellite-stable, grade 2 endometrioid endometrial carcinoma cohorts, in vitro NT5E (CD73) knockout/knockdown, and single-cell and spatial analyses, we show that cancer cell CD73 loss promotes a dual inflammatory and immunosuppressive microenvironment. Cancer cell CD73 loss was associated with increased lymphovascular space invasion and worse recurrence-free and overall survival, whereas stromal CD73 expression did not correlate with outcomes. CD73 downregulation induced pro-inflammatory gene expression, which strongly correlated with upregulation of immunosuppressive genes, including CD274 (PD-L1), suggesting a compensatory mechanism limiting antitumor immunity. Tumors with low cancer cell CD73 exhibited higher PD-L1 expression that correlated with increased CD3+ T-cell infiltration, reflecting an immune-engaged but checkpoint-restrained microenvironment. Single-cell analyses demonstrated that NT5E+ nonimmune cells in immune-responsive clusters were three times less likely to express CD274. In clinically relevant low-grade endometrial carcinoma models, functional studies confirmed that CD73 loss promoted both pro-inflammatory and immunosuppressive programs. These results reveal a context-specific role for CD73 in shaping the immune landscape of low-grade endometrial carcinoma that is distinct from its function in other solid tumors.

Significance:: Unlike most cancers, in which CD73 drives immunosuppression via overexpression, we show that cancer cell CD73 loss promotes an inflammatory yet compensatory immunosuppressive microenvironment in low-grade endometrial carcinoma, revealing a context-specific role. CD73 loss in endometrial carcinoma therefore may be as immunologically significant as its overexpression in other cancers.

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Cite

BibTeXRIS
BibTeX
@article{lee2026cancer,
  title = {{Cancer Cell CD73 Loss Promotes a Dual Inflammatory and Immunosuppressive Microenvironment in Endometrial Carcinoma}},
  author = {Hannah N. Lee and Xingyuan Zhang and Suzanne M. Crumley and Emily M. Rabjohns and Luan H. Phan and Di Wu and Russell R. Broaddus and Cyrus Vaziri and Jessica L. Bowser},
  journal = {Cancer Research Communications},
  year = {2026},
  month = nov,
  doi = {10.1158/2767-9764.crc-26-0167},
  url = {https://doi.org/10.1158/2767-9764.crc-26-0167},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Cancer Cell CD73 Loss Promotes a Dual Inflammatory and Immunosuppressive Microenvironment in Endometrial Carcinoma
AU  - Hannah N. Lee
AU  - Xingyuan Zhang
AU  - Suzanne M. Crumley
AU  - Emily M. Rabjohns
AU  - Luan H. Phan
AU  - Di Wu
AU  - Russell R. Broaddus
AU  - Cyrus Vaziri
AU  - Jessica L. Bowser
PY  - 2026
DA  - 2026/11/05
JO  - Cancer Research Communications
DO  - 10.1158/2767-9764.crc-26-0167
UR  - https://doi.org/10.1158/2767-9764.crc-26-0167
AB  - CD73 is an emerging immunotherapy target that is overexpressed in many tumors and generates an adenosine-rich microenvironment to suppress antitumor immunity. In low-grade endometrial carcinoma, CD73 expression varies, and its impact on tumor immunobiology is unknown. Using two microsatellite-stable, grade 2 endometrioid endometrial carcinoma cohorts, in vitro NT5E (CD73) knockout/knockdown, and single-cell and spatial analyses, we show that cancer cell CD73 loss promotes a dual inflammatory and immunosuppressive microenvironment. Cancer cell CD73 loss was associated with increased lymphovascular space invasion and worse recurrence-free and overall survival, whereas stromal CD73 expression did not correlate with outcomes. CD73 downregulation induced pro-inflammatory gene expression, which strongly correlated with upregulation of immunosuppressive genes, including CD274 (PD-L1), suggesting a compensatory mechanism limiting antitumor immunity. Tumors with low cancer cell CD73 exhibited higher PD-L1 expression that correlated with increased CD3+ T-cell infiltration, reflecting an immune-engaged but checkpoint-restrained microenvironment. Single-cell analyses demonstrated that NT5E+ nonimmune cells in immune-responsive clusters were three times less likely to express CD274. In clinically relevant low-grade endometrial carcinoma models, functional studies confirmed that CD73 loss promoted both pro-inflammatory and immunosuppressive programs. These results reveal a context-specific role for CD73 in shaping the immune landscape of low-grade endometrial carcinoma that is distinct from its function in other solid tumors.  Significance:: Unlike most cancers, in which CD73 drives immunosuppression via overexpression, we show that cancer cell CD73 loss promotes an inflammatory yet compensatory immunosuppressive microenvironment in low-grade endometrial carcinoma, revealing a context-specific role. CD73 loss in endometrial carcinoma therefore may be as immunologically significant as its overexpression in other cancers.
SN  - 2767-9764
ER  -