Systemic and local chronic inflammation and hormone disposition promote a tumor-permissive environment for breast cancer in older women

  1. Neil Carleton
  2. Sanghoon Lee
  3. Ruxuan Li
  4. Jian Zou
  5. Daniel D Brown
  6. Jagmohan Hooda
  7. Alexander Chang
  8. Rahul Kumar
  9. Linda R Klei
  10. Lora H Rigatti
  11. Joseph Newsome
  12. Dixcy Jaba Sheeba John Mary
  13. Jennifer M Atkinson
  14. Raymond E West
  15. Thomas D Nolin
  16. Patrick J Oberly
  17. Ziyu Huang
  18. Donald Poirier
  19. Emilia J Diego
  20. Peter C Lucas
  21. George Tseng
  22. Michael T Lotze
  23. Priscilla F McAuliffe
  24. Ioannis K Zervantonakis
  25. Steffi Oesterreich
  26. Adrian V Lee

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Abstract

Estrogen receptor positive (ER+) breast cancer is the most common subtype of breast cancer and is an age-related disease. The peak incidence of diagnosis occurs around age 70, even though these post-menopausal patients have low circulating levels of estradiol (E2). Despite the hormone sensitivity of age-related tumors, we have a limited understanding of the interplay between systemic and local hormones, chronic inflammation, and immune changes that contribute to the growth and development of these tumors. Here, we show that aged F344 rats treated with the dimethylbenz(a)anthracene / medroxyprogestrone acetate (DMBA/MPA) carcinogen develop more tumors at faster rates than their younger counterparts, suggesting that the aged environment promotes tumor initiation and impacts growth. Single-nuclei RNA-seq (snRNA-seq) of the tumors showed broad local immune dysfunction that was associated with circulating chronic inflammation. Across a broad cohort of specimens from patients with ER+ breast cancer and age-matched donors of normal breast tissue, we observe that even with an estrone (E1)-predominant estrogen disposition in the systemic circulation, tumors in older patients increase HSD17B7 expression to convert E1 to E2 in the tumor microenvironment (TME) and have local E2 levels similar to pre-menopausal patients. Concurrently, trackable increases in several chemokines, defined most notably by CCL2, promote a chronically inflamed but immune dysfunctional TME. This unique milieu in the aged TME, characterized by high local E2 and chemokine-enriched chronic inflammation, promotes both accumulation of tumor-associated macrophages (TAMs), which serve as signaling hubs, as well as polarization of TAMs towards a CD206+/PD-L1+, immunosuppressive phenotype. Pharmacologic targeting of estrogen signaling (either by HSD17B7 inhibition or with fulvestrant) and chemokine inflammation both decrease local E2 and prevent macrophage polarization. Overall, these findings suggest that chronic inflammation and hormonal disposition are critical contributors to the age-related nature of ER+ breast cancer development and growth and offer potential therapeutic insight to treat these patients.

Translational Summary

We uncover the unique underpinnings establishing how the systemic host environment contributes to the aged breast tumor microenvironment, characterized by high local estradiol and chronic inflammation with immune dysregulation, and show that targeting avenues of estrogen conversion and chronic inflammation work to restore anti-tumor immunity.

Graphical Abstract

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  1. PREreview

    This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/14841258.

    Does the introduction explain the objective of the research presented in the preprint? Yes The topic and the introduction are well aligned. The introduction explains the broader perspective of the topic and streams it down to the existing gap and shows the researchers' objective of the study.
    Are the methods well-suited for this research? Highly appropriate
    Are the conclusions supported by the data? Somewhat supported
    Are the data presentations, including visualizations, well-suited to represent the data? Highly appropriate and clear
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Very clearly
    Is the preprint likely to advance academic knowledge? Highly likely
    Would it benefit from language editing? No
    Would you recommend this preprint to others? Yes, but it needs to be improved We recommend that the preprint should be presented in the common standard format to make it easy to follow, i.e. abstract, introduction, methodologies, results, discussion/conclusion, etc.
    Is it ready for attention from an editor, publisher or broader audience? Yes, after minor changes

    Competing interests

    The authors declare that they have no competing interests.

  2. Version published to 10.1101/2024.10.18.616978 on bioRxiv