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860 Targeting immunosuppressive macrophages overcomes PARP-inhibitor resistance in BRCA1-associated triple-negative breast cancer
  1. Anita Mehta1,
  2. Emily Cheney1,
  3. Christina Hartl1,
  4. Constantia Pantelidou1,
  5. Madison Oliwa2,
  6. Jessica Castrillon1,
  7. Jia-Ren Lin3,
  8. Katie Hurst4,
  9. Mateus de Oliveira Taveira5,
  10. Nathan Johnson3,
  11. William Oldham6,
  12. Marian Kalocsay3,
  13. Matthew Berberich3,
  14. Sarah Boswell3,
  15. Aditi Kothari1,
  16. Shawn Johnson1,
  17. Deborah Dillon7,
  18. Mikel Lipschitz7,
  19. Scott Rodig7,
  20. Sandro Santagata7,
  21. Judy Garber1,
  22. Nadine Tung8,
  23. José Yélamos9,
  24. Jessica Thaxton4,
  25. Elizabeth Mittendorf1,
  26. Peter Sorger3,
  27. Geoffrey Shapiro1 and
  28. Jennifer Guerriero1
  1. 1Dana Farber Cancer Institute, Boston, MA, USA
  2. 2Dana-Farber Cancer Institute and Harvard, Boston, USA
  3. 3Harvard Medical School, Boston, MA, USA
  4. 4Medical University of South Carolina, Charleston, SC, USA
  5. 5A.C. Camargo Cancer Center, São Paulo, Brazil
  6. 6Brigham and Women’s Hospital and Harvard, Boston, MA, USA
  7. 7Brigham and Women’s Hospital and Harvard, Boston, MA, USA
  8. 8Beth Israel Deaconess Medical Center, Boston, MA, USA
  9. 9Medical Research Institute, Barcelona, Spain


Background Despite objective responses to PARP inhibition and improvements in progression-free survival compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory.

Methods Using high dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in BRCA-associated TNBC. Through multi-omics profiling we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming driven by the sterol regulatory element-binding protein 1 (SREBP-1) pathway.

Results Combined PARP inhibitor therapy with CSF-1R blocking antibodies significantly enhanced innate and adaptive anti-tumor immunity and extends survival in BRCA-deficient tumors in vivo and is mediated by CD8+ T-cells.

Conclusions Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate combined PARP inhibition and macrophage targeting therapy induces a durable reprogramming of the tumor microenvironment, thus constituting a promising therapeutic strategy for TNBC.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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