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Expression pattern, regulation, and clinical significance of TOX in breast cancer

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Abstract

Thymocyte selection-associated high mobility group box protein (TOX) is a transcription factor implicated in the regulation of T cell exhaustion during chronic infection and cancer. While TOX is being targeted for cancer immunotherapy, limited information is available about its significance in breast cancer and other solid tumors. We performed a comprehensive analysis of TOX gene expression, its epigenetic regulation, protein localization, relation to tumor infiltrating immune cell composition, and prognostic significance in breast cancer using publicly available datasets. Our results suggest an inverse correlation between TOX expression and DNA methylation in tumor cells. However, its expression is elevated in tumor infiltrating immune cells (TIICs), which may compensates for the total TOX levels in the tumor as a whole. Furthermore, higher TOX levels in tumors are associated with T cell exhaustion signatures along with presence of active inflammatory response, including elevated levels of T cell effector cytokines. Survival analysis also confirmed that higher expression of TOX is associated with better prognosis in breast cancer. Therefore, expression of TOX may serve as a novel prognostic marker for this malignancy.

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All data sources are freely available to access and have been mentioned in “Materials and methods” section.

Abbreviations

APCs:

Antigen presenting cells

CNA:

Copy number alteration

CK6 :

Cytokeratin 6

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

ER:

Estrogen receptor

GEO:

Gene Expression Omnibus

HMG:

High mobility group

HER2:

Human epidermal growth factor receptor 2

HPA:

Human Protein Atlas

ICPs:

Immune checkpoint proteins

PR:

Progesterone receptor

PD-1:

Programmed cell death protein 1

PD-L1:

Programmed death-ligand 1

TCGA:

The Cancer Genome Atlas

TOX:

Thymocyte selection-associated high mobility group box protein

TIICs:

Tumor infiltrating immune cells

TME:

Tumor microenvironment

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Funding

This study was supported by grants from Indian Council of Medical Research (ICMR, India), Grant number 2019-2914 to SSC.

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Authors and Affiliations

  1. Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India

    Mohit Arora & Shyam S. Chauhan

  2. Laboratory Oncology Unit, Dr. BRA-IRCH, All India Institute of Medical Sciences, New Delhi, India

    Sarita Kumari, Jay Singh & Anita Chopra

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  1. Mohit Arora
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  2. Sarita Kumari
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  3. Jay Singh
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  5. Shyam S. Chauhan
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Contributions

MA conceptualized the study. SSC supervised the study and arranged funding. MA, SK, JS and AC performed data curation, interpretation and statistical analysis. SK performed the validation of all results. MA wrote the original manuscript. SK, AC and SSC edited the manuscript. All the authors have approved the manuscript.

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Correspondence to Shyam S. Chauhan.

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Arora, M., Kumari, S., Singh, J. et al. Expression pattern, regulation, and clinical significance of TOX in breast cancer. Cancer Immunol Immunother 70, 349–363 (2021). https://doi.org/10.1007/s00262-020-02689-3

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