Buenos Aires
Breast Cancer
Symposium

BA-BCS 2024

September 3 – 6, 2024

IFIBYNE Auditorium, FCEN-UBA

 

Progesterone promotes triple-negative breast cancer metastasis through RANKL-expressing Treg cells

TOMAS DALOTTO1, PERROTTA RAMIRO1, ROSA MORALES1, SABRINA GATTO1, GABRIEL RABINOVICH1, MARIANA SALATINO1

1.IBYME

Presenting Autor:
Tomas DAlotto

Glicomedicina-IBYME

Unresectable metastatic triple negative (TN) breast cancer is an aggressive disease with poor outcome and a short overall survival affecting about 15-20% of women diagnosed with breast cancer. Progestins can shape the immune response favoring a tumor-supportive rather than an anti-tumor immune response. In this sense, hormone replacement regimens and certain hormone-based contraceptives, has been associated with an increased risk of aggressive breast cancer and recurrency. Here we studied in a mouse tumor model of TNBC (4T1) whether progestins can influence tumor progression by enhancing the suppressive activity of protumoral immune cells within the tumor microenvironment in a tumor cell-independent fashion. Progestin treatment using either MPA, Progesterone or levonorgestrel promoted an increase in the frequency of tumor-infiltrating effector Foxp3+ Tregs. Interestingly, lung metastatic burden was higher in progestin-treated mice, which was drastically reverted upon Treg cell depletion. Adoptive transfer of progestin-educated Tregs elicited an increase in the number of lung metastasis in Treg-depleted mice. Mechanistically, progestins activated progesterone membrane receptors on Tregs, enhancing their immunosuppressive activity and production of RANKL. We show that Tregs-derived RANKL acting directly on TN tumor cells stimulated epithelial to mesenchymal transition and a stem-like phenotype ultimately boosting their invasive/metastatic capacity. Finally, in vivo, blockade of RANKL with a monoclonal antibody impaired the metastatic potential of 4T1 tumors induced by progestins and progestin-educated Tregs. Our findings highlight the relevance of progestins in modulating antitumor immune response and harnessing immunosurveillance in the tumor microenvironment and describe a mechanism through which Tregs could directly promote a metastatic and aggressive phenotype on TNBC cells.