MORF4L2 induces immunosuppressive microenvironment and immunotherapy resistance through GRHL2/MORF4L2/H4K12Ac/CSF1 axis in triple-negative breast cancer

Xin-Yi Sui; Shuo-Wen Cao; Xiao-Qing Song; Xi-Yu Liu; Chao Chen; Qingya Yan; Zhi-Qing Wang; Wen-Juan Zhang; Lin-Xiaoxi Ma; Xi Jin; Ding Ma; Yi Xiao; Song-Yang Wu; Ying Xu; Zhi-Ming Shao; Lei Fan

doi:10.1186/s40364-024-00719-1

MORF4L2 induces immunosuppressive microenvironment and immunotherapy resistance through GRHL2/MORF4L2/H4K12Ac/CSF1 axis in triple-negative breast cancer

Biomark Res. 2025 Jan 9;13(1):6. doi: 10.1186/s40364-024-00719-1.

Authors

Xin-Yi Sui^#^{1

2}, Shuo-Wen Cao^#^{1

2}, Xiao-Qing Song^#^{1

2}, Xi-Yu Liu^#^{1

2}, Chao Chen^{1

2}, Qingya Yan³, Zhi-Qing Wang^{1

2}, Wen-Juan Zhang^{1

2}, Lin-Xiaoxi Ma^{1

2}, Xi Jin^{1

2}, Ding Ma^{1

2}, Yi Xiao^{1

2}, Song-Yang Wu^{1

2}, Ying Xu^{1

2}, Zhi-Ming Shao^{4

5}, Lei Fan^{6

7}

Affiliations

¹ Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
² Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.
⁴ Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. [email protected].
⁵ Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
⁶ Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. [email protected].
⁷ Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].

^# Contributed equally.

PMID: 39780291
DOI: 10.1186/s40364-024-00719-1

Abstract

Background: Although immunotherapy has achieved great progress in advanced triple-negative breast cancer (TNBC), there are still numerous patients who do not benefit from immunotherapy. Therefore, identification of the key molecule that induces immune escape and clarification of its specific mechanism in TNBC are urgently needed.

Methods: In this research, single cell sequencing and bulk sequencing were conducted for biomarker screening. Immunohistochemistry, multiplex immunofluorescence, and orthotopic TNBC tumor model were applied in identifying the key molecule driving immune escape. At the mechanical level, RNA sequencing, in vitro co-culturing system, flow cytometry, Western blotting, ELISA, and real-time qPCR were carried out.

Results: Mortality factor 4 like 2 (MORF4L2) expression is significantly up-regulated among patients who developed anti-PD1 resistance. MORF4L2 enhances anti-PD1 resistance by inducing the chemotaxis of macrophage infiltration and promoting their polarization towards the alternative activation phenotype (M2), thus creating an immunosuppressive microenvironment. Mechanistically, MORF4L2 actes as part of NuA4 histone acetyltransferase (HAT) complex, contributes to to histone 4 lysine 12 acetylation (H4K12Ac) and activates the downstream transcription of macrophage colony-stimulating factor (CSF1). CSF1 is secreted by tumor cells and binds to the macrophage-surface CSF1 receptor (CSF1R), which chemotactically converted and polarized macrophages to the M2 phenotype. Furthermore, we revealed that grainyhead like transcription factor 2 (GRHL2) could promote MORF4L2 transcription by binding to the MORF4L2 enhancer region. Notably, BLZ549, an inhibitor of CSF1R, restored the anti-PD1 sensitivity by blocking the GRHL2/MORF4L2/H4K12Ac/CSF1 axis.

Conclusions: GRHL2/MORF4L2/H4K12Ac/CSF1 axis plays an important role in anti-PD1 resistance. CSF1R inhibitors can reverse GRHL2/MORF4L2-mediated anti-PD1 resistance.

Keywords: Anti-PD1; Combination therapy; Histone 4 lysine 12 acetylation; Mortality factor 4 like 2; Triple-negative breast cancer; Tumor microenvironment.

Abstract

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