Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Tumor-Intrinsic Enhancer of Zeste Homolog 2 Controls Immune Cell Infiltration, Tumor Growth and Lung Metastasis in a Triple Negative Breast Cancer Model

Lenore Monterroza
,
Maria M. Parrilla
,
Sarah G. Samaranayake
,
Dormarie E. Rivera-Rodriguez
,
Sung Bo Yoon
,
Ramireddy Bommireddy
,
Justin Hosten
,
Luisa Cervantes Barragan
,
Adam Marcus
,
Brian S. Dobosh
,
Periasamy Selvaraj
* ,
Rabindra Tirouvanziam
* ORCID logo
Version 1 : Received: 2 April 2024 / Approved: 3 April 2024 / Online: 3 April 2024 (11:06:57 CEST)

How to cite: Monterroza, L.; Parrilla, M.M.; Samaranayake, S.G.; Rivera-Rodriguez, D.E.; Yoon, S.B.; Bommireddy, R.; Hosten, J.; Barragan, L.C.; Marcus, A.; Dobosh, B.S.; Selvaraj, P.; Tirouvanziam, R. Tumor-Intrinsic Enhancer of Zeste Homolog 2 Controls Immune Cell Infiltration, Tumor Growth and Lung Metastasis in a Triple Negative Breast Cancer Model. Preprints 2024, 2024040261. https://doi.org/10.20944/preprints202404.0261.v1 Monterroza, L.; Parrilla, M.M.; Samaranayake, S.G.; Rivera-Rodriguez, D.E.; Yoon, S.B.; Bommireddy, R.; Hosten, J.; Barragan, L.C.; Marcus, A.; Dobosh, B.S.; Selvaraj, P.; Tirouvanziam, R. Tumor-Intrinsic Enhancer of Zeste Homolog 2 Controls Immune Cell Infiltration, Tumor Growth and Lung Metastasis in a Triple Negative Breast Cancer Model. Preprints 2024, 2024040261. https://doi.org/10.20944/preprints202404.0261.v1

Abstract

Triple-negative breast cancer (TNBC) is an aggressive and highly metastatic type of tumor. TNBC is often enriched in tumor-infiltrating neutrophils (TINs), which support cancer growth in part by counteracting tumor-infiltrating lymphocytes (TILs). Prior studies identified the enhancer of zeste homolog 2 (EZH2) as a pro-tumor methyltransferase in primary and metastatic TNBC. We hypothesized that EZH2 inhibition in TNBC cells per se would exert anti-tumor activity by altering the tumor immune microenvironment. To test this hypothesis, we used CRISPR to generate EZH2-knockout (KO) and overexpressing lines from parent (wild-type -WT) 4T1 cells, an established murine TNBC model. In vitro, EZH2 KO and OE cells showed little change in replicative capacity and invasiveness, but marked changes in surface marker profile and cytokine/chemokine secretion compared to WT cells. On in vivo injection, EZH2 KO cells showed significantly reduced primary tumor growth and a 10-fold decrease in lung metastasis compared to WT cells, while EZH2 OE cells were unchanged. Compared to WT tumors, TIN:TIL ratios were greatly reduced in EZH2 KO tumors but unchanged in EZH2 OE tumors. Our findings show a tumor-intrinsic role of EZH2 in the 4T1 TNBC model in regulating TIN/TIL poise, primary tumor progression and lung metastasis in vivo.

Keywords

CD4+ T-cell; CD8+ T-cell; invasion; myeloid-derived suppressor cell; triple-negative breast cancer; tumor-infiltrating neutrophils

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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