Neoplastic immune mimicry is a generalizable phenomenon in breast cancer and epithelial CD69 enables early tumor progression

Berens, E. B.; Khou, S.; Huang, E.; Hoffman, A.; Johnson, B.; Kirchberger, N.; Sivagnanam, S.; Calistri, N. L.; Derrick, D.; Liby, T. A.; McLean, I. C.; Alanizi, A. A.; Ozmen, F.; Ozmen, T. Y.; Mills, G. B.; Hwang, E. S.; Schedin, P. J.; Gonzalez, H.; Werb, Z.; Heiser, L. M.; Coussens, L. M.

doi:10.1101/2025.01.17.633673

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bioRxiv · 10.1101/2025.01.17.633673

Neoplastic immune mimicry is a generalizable phenomenon in breast cancer and epithelial CD69 enables early tumor progression

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Abstract

Dedifferentiation programs are commonly enacted during breast cancer progression to enhance tumor cell fitness. Increased cellular plasticity within the neoplastic compartment of tumors correlates with disease aggressiveness, often culminating in greater resistance to cytotoxic therapies or augmented metastatic potential. Here we report that subpopulations of dedifferentiated neoplastic breast epithelial cells express canonical leukocyte cell surface receptor proteins and have thus named this cellular program "immune mimicry." We document neoplastic cells engaging in immune mimicry within public human breast tumor single-cell RNA-seq datasets, histopathological breast tumor specimens, breast cancer cell lines, as well as in murine transgenic and cell line-derived mammary cancer models. Immune-mimicked neoplastic cells harbor hallmarks of dedifferentiation and are enriched in treatment-resistant and high-grade breast tumors. We corroborated these observations in aggressive breast cancer cell lines where anti-proliferative cytotoxic chemotherapies drove epithelial cells toward immune mimicry. Moreover, in subsequent proof-of-concept studies, we demonstrate that expression of the CD69 leukocyte activation protein by neoplastic cells confers a proliferative advantage that facilitates early tumor growth and therefore conclude that neoplastic breast epithelial cells upregulating leukocyte surface receptors potentiate malignancy. Moving forward, neoplastic immune mimicry should be evaluated for prognostic utility in additional breast cancer cohorts to determine its potential for patient stratification. Future research should evaluate correlates with distal metastases, progression-free survival, overall survival, and therapeutic response/resistance. Statement of SignificanceNeoplastic breast epithelial cells express surface receptors canonically attributed to leukocytes and are associated with therapy resistance and aggressive tumor behavior.

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Berens, E. B., Khou, S., Huang, E., Hoffman, A., Johnson, B., Kirchberger, N., Sivagnanam, S., Calistri, N. L., Derrick, D., Liby, T. A., McLean, I. C., Alanizi, A. A., Ozmen, F., Ozmen, T. Y., Mills, G. B., Hwang, E. S., Schedin, P. J., Gonzalez, H., Werb, Z., Heiser, L. M., Coussens, L. M.. 2025-01-22. Neoplastic immune mimicry is a generalizable phenomenon in breast cancer and epithelial CD69 enables early tumor progression. https://doi.org/10.1101/2025.01.17.633673

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