Endocrine therapy synergizes with SMAC mimetics to potentiate antigen presentation and tumor regression in hormone receptor-positive breast cancer

  • Cancer Res. 2023 Jul 14;CAN-23-1711. doi: 10.1158/0008-5472.CAN-23-1711.
Francisco Hermida-Prado  1 ,  Yingtian Xie  1 ,  Shira Sherman  2 ,  Zsuzsanna Nagy  3 ,  Douglas Russo  4 ,  Tara Akhshi  5 ,  Zhengtao Chu  6 ,  Avery Feit  7 ,  Marco Campisi  1 ,  Minyue Chen  5 ,  Agostina Nardone  8 ,  Cristina Guarducci  2 ,  Klothilda Lim  1 ,  Alba Font-Tello  1 ,  Irene Lee  9 ,  Juana García-Pedrero  10 ,  Israel Canadas  11 ,  Judith Agudo  2 ,  Ying Huang  5 ,  Tal Sella  12 ,  Qingchun Jin  1 ,  Nabihah Tayob  13 ,  Elizabeth A Mittendorf  14 ,  Sara M Tolaney  13 ,  Xintao Qiu  1 ,  Henry Long  1 ,  William F Symmans  15 ,  Jia-Ren Lin  16 ,  Sandro Santagata  17 ,  Isabelle Bedrosian  18 ,  Denise A Yardley  19 ,  Ingrid A Mayer  20 ,  Edward T Richardson  14 ,  Giacomo Oliveira  2 ,  Catherine J Wu  1 ,  Eugene F Schuster  21 ,  Mitch Dowsett  22 ,  Alana L Welm  23 ,  David Barbie  1 ,  Otto Metzger  2 ,  Rinath Jeselsohn  1
Affiliations
  • 1. Dana-Farber Cancer Institute, Boston, MA, United States.
  • 2. Dana-Farber Cancer Institute, Boston, United States.
  • 3. Dana-Farber/Harvard Cancer Center, Boston, MA, United States.
  • 4. Dana-Farber/Harvard Cancer Center, Boston, United States.
  • 5. Dana-Farber Cancer Institute, United States.
  • 6. Huntsman Cancer Institute, United States.
  • 7. Albert Einstein College of Medicine, Bronx, NY, United States.
  • 8. Dana-Farber Cancer Institute, Boston, Ma, United States.
  • 9. AbbVie (United States), North Chicago, IL, United States.
  • 10. Central University Hospital of Asturias, Oviedo, Asturias, Spain.
  • 11. Fox Chase Cancer Center, Philadelphia, PA, United States.
  • 12. Sheba Medical Center, Ramat Gan, Israel.
  • 13. Dana-Farber Cancer Institute, Boston, Massachusetts, United States.
  • 14. Brigham and Women's Hospital, Boston, MA, United States.
  • 15. The University of Texas MD Anderson Cancer Center, Houston, 77030, United States.
  • 16. Harvard Medical School, Boston, MA, United States.
  • 17. Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
  • 18. The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
  • 19. Sarah Cannon Research Center, Nashville, TN, United States.
  • 20. AstraZeneca (United States), Gaithersburg, MD, United States.
  • 21. Institute of Cancer Research, London, United Kingdom.
  • 22. Royal Marsden Hospital, London, United Kingdom.
  • 23. Huntsman Cancer Institute, Salt Lake City, UT, United States.
PMID: 37450351 DOI: 10.1158/0008-5472.CAN-23-1711
Abstract

Immunotherapies have yet to demonstrate significant efficacy in the treatment of hormone receptor positive (HR+) Breast Cancer. Given that endocrine therapy (ET) is the primary approach for treating HR+ Breast Cancer, we investigated the effects of ET on the tumor immune microenvironment (TME) in HR+ Breast Cancer. Spatial proteomics analysis of primary HR+ Breast Cancer samples obtained at baseline and after ET from patients enrolled in a neoadjuvant clinical trial (NCT02764541) indicated that ET upregulated B2-microglobulin and influenced the TME in a manner that promotes enhanced immunogenicity. To gain a deeper understanding of the underlying mechanisms, the intrinsic effects of ET on Cancer cells were explored, which revealed that ET plays a crucial role in facilitating the chromatin binding of RelA, a key component of the NF-κB complex. Consequently, heightened NF-κB signaling enhanced the response to interferon-gamma, leading to the upregulation of β2-microglobulin and other antigen presentation-related genes. Further, modulation of NF-κB signaling using a SMAC-mimetic in conjunction with ET augmented T-cell migration and enhanced MHC-I specific T-cell mediated cytotoxicity. Remarkably, the combination of ET and SMAC-mimetics, which also block pro-survival effects of NF-κB signaling through the degradation of inhibitors of Apoptosis (IAP) proteins, elicited tumor regression through cell-autonomous mechanisms, providing additional support for their combined use in HR+ Breast Cancer.

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