Theranostics 2022; 12(8):3584-3600. doi:10.7150/thno.72192 This issue

Research Paper

TRIB1 regulates tumor growth via controlling tumor-associated macrophage phenotypes and is associated with breast cancer survival and treatment response

Taewoo Kim1, Jessica Johnston1, Sonia Castillo-Lluva2, Francisco J. Cimas3, Stephen Hamby4, The Cardiogenics Consortium*, Santiago Gonzalez-Moreno5, Pedro Villarejo-Campos6, Alison H Goodall4, Guillermo Velasco2, Alberto Ocana3, Munitta Muthana7, Endre Kiss-Toth1,8✉

1. Department of Infection, Immunity and Cardiovascular Diseases, University of Sheffield Medical School, Sheffield, S10 2RX, UK.
2. Department of Biochemistry and Molecular Biology, Complutense University and Instituto de Investigación Sanitaria Clínico San Carlos (IdISSC), 28040, Madrid, Spain.
3. Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria Clínico San Carlos (IdISSC), Madrid and Universidad de Castilla La Mancha (UCLM), Albacete, Spain.
4. Department of Cardiovascular Sciences, Glenfield Hospital, University of Leicester and Leicester NIHR Biomedical Research Centre, Leicester, UK.
5. MD Anderson Cancer Center Madrid, Madrid, Spain.
6. Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain.
7. Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, S10 2RX, UK.
8. Biological Research Centre of the Hungarian Academy of Sciences, Temesvari krt. 62, Szeged, 6726, Hungary.
*Membership of the Cardiogenics Consortium appears in the Supplementary files.

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Citation:
Kim T, Johnston J, Castillo-Lluva S, Cimas FJ, Hamby S, The Cardiogenics Consortium*, Gonzalez-Moreno S, Villarejo-Campos P, Goodall AH, Velasco G, Ocana A, Muthana M, Kiss-Toth E. TRIB1 regulates tumor growth via controlling tumor-associated macrophage phenotypes and is associated with breast cancer survival and treatment response. Theranostics 2022; 12(8):3584-3600. doi:10.7150/thno.72192. Available from https://www.thno.org/v12p3584.htm

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Abstract

Graphic abstract

Molecular mechanisms that regulate tumor-associated macrophage (TAM) phenotype and function are incompletely understood. The pseudokinase TRIB1 has been reported as a regulator of macrophage phenotypes, both in mouse and human systems.

Methods: Bioinformatic analysis was used to investigate the link between TRIB1 expression in breast cancer and therapeutic response to chemotherapy. In vivo models of breast cancer included immune-competent mice to characterize the consequences of altered (reduced or elevated) myeloid Trib1 expression on tumor growth and composition of stromal immune cell populations.

Results: TRIB1 was highly expressed by TAMs in breast cancer and high TRIB1 expression correlated with response to chemotherapy and patient survival. Both overexpression and knockout of myeloid Trib1 promote mouse breast tumor growth, albeit through different molecular mechanisms. Myeloid Trib1 deficiency led to an early acceleration of tumor growth, paired with a selective reduction in perivascular macrophage numbers in vivo and enhanced oncogenic cytokine expression in vitro. In contrast, elevated levels of Trib1 in myeloid cells led to an increased late-stage mammary tumor volume, coupled with a reduction of NOS2 expressing macrophages and an overall reduction of macrophages in hypoxic tumor regions. In addition, we show that myeloid Trib1 is a previously unknown, negative regulator of the anti-tumor cytokine IL-15, and that increased myeloid Trib1 expression leads to reduced IL-15 levels in mammary tumors, with a consequent reduction in the number of T-cells that are key to anti-tumor immune responses.

Conclusions: Together, these results define a key role for TRIB1 in chemotherapy responses for human breast cancer and provide a mechanistic understanding for the importance of the control of myeloid TRIB1 expression in the development of this disease.

Keywords: Breast cancer, tumor associated macrophages, tribbles, TRIB1, response to chemotherapy, interleukin 15