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

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

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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