RHOA Deletion Downregulates CD19 and Promotes Dysfunctional Immune Microenvironments in CAR-T Resistant Large B-cell Lymphomas

  • Blood Cancer Discov. 2026 Sep 18:10.1158/2643-3230.BCD-25-0482. doi: 10.1158/2643-3230.BCD-25-0482.
Austin D Newsam  1 ,  Bachisio Ziccheddu  2 ,  Abdessamad A Youssfi  1 ,  Venu Venkatarame Gowda Saralamma  3 ,  Santiago Foos-Russ  4 ,  Daniel E Tsai  5 ,  Isaiah Sheffield-Veney  4 ,  Adithi Jeevan  4 ,  Paola Manara  1 ,  Yitzhar E Goretsky  6 ,  David M Suissa  4 ,  Marco Vincenzo Russo  1 ,  Nikolai Fattakhov  1 ,  David Carmona-Berrio  7 ,  Natalia Campos Gallego  8 ,  Caroline A Coughlin  1 ,  Anya K Sondhi  9 ,  Evan R Roberts  1 ,  Jay Y Spiegel  10 ,  Juan Pablo Alderuccio  11 ,  Catalina Amador  5 ,  Daniel Bilbao  12 ,  David G Coffey  13 ,  Michael D Jain  14 ,  Francesco Maura  2 ,  Frederick L Locke  15 ,  Jonathan H Schatz  1
Affiliations
  • 1. University of Miami Miller School of Medicine Miami, FL United States.
  • 2. Memorial Sloan Kettering Cancer Center New York, NY United States.
  • 3. Sylvester Comprehensive Cancer Center United States.
  • 4. University of Miami United States.
  • 5. University of Miami Miami, Florida United States.
  • 6. Keck Hospital of USC United States.
  • 7. University of Miami Miami, FL United States.
  • 8. Sylvester Comprehensive Cancer Center Miami, FL United States.
  • 9. University of Miami Hospital Miami United States.
  • 10. Sylvester Comprehensive Cancer Center Miami United States.
  • 11. Sylvester Comprehensive Cancer Center, University of Miami School of Medicine Miami, FL United States.
  • 12. University of Miami Miller School of Medicine Miami, Florida United States.
  • 13. University of Miami Health System Miami, FL United States.
  • 14. Moffitt Cancer Center Tampa, Florida United States.
  • 15. Moffitt Cancer Center Tampa, FL United States.
PMID: 42757854 DOI: 10.1158/2643-3230.BCD-25-0482
Abstract

CD19-directed chimeric antigen receptor (CAR)-T cells are breakthrough therapies for large B-cell lymphomas, but fewer than half of patients achieve durable responses. We previously showed RHOA deletions are enriched in progressing cases, but the role of RHOA deficiency is poorly defined despite frequent occurrence in newly diagnosed disease. Here we show RHOA loss downregulates CD19, promoting cell-intrinsic resistance to CAR-19 in vitro and in vivo. CD19 decline, however, provides an incomplete explanation of resistance and would not explain high frequency of the deletion in newly diagnosed cases. We therefore performed single-cell assessments of immunocompetent RHOA-deficient lymphoma microenvironments, revealing remarkable concordance with features in CAR-19-resistant patients. Despite increased microenvironmental production of interferon gamma (IFNγ), RHOA-deficient tumor cells themselves show impaired response to the cytokine including failed induction of Class I MHC molecules. Overall, we describe for the first time how a single-gene alteration recurrent in CAR-19-resistant lymphoma contributes to treatment failures.

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