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In situ expression of IFN-γ-inducible T cell α chemoattractant in breast cancer mounts an enhanced specific anti-tumor immunity which leads to tumor regression

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Abstract

Increased evidence indicates that chemokines are involved in tumor growth. ITAC, a key member of chemokines, possesses the ability to recruit T cells and enhance immune responses. Therefore, ITAC might contribute to antitumor immunity. In this study, we evaluated the relationship between the expression of ITAC and human breast cancer advancement. We further investigated whether forced expression of ITAC in tumor sites could mediate enhanced antitumor immunity in a murine breast cancer model. Results showed that ITAC expression level was down-regulated in 31 breast cancer specimens compared to normal mammary tissues, and associated negatively with the stages of breast cancer. Contrarily, forced expression of ITAC in murine 4T1 tumor cells resulted in tumor regression after initial growth upon injection into naïve Balb/c mice. More lymphocytes were recruited to the site of tumor inoculated by 4T1-ITAC and more than 80% of these T cells expressed the ITAC receptor, CXCR3. ITAC-recruited TILs exhibited 4T1-specific proliferation and cytotoxicity, and an increased IFN-γ but decreased IL-4 production. Importantly, forced expression of ITAC in 4T1 tumor nodules inhibited tumor growth. These findings demonstrated that the decreased expression of ITAC is associated with the advancement of breast cancer in patients. Forced expression of ITAC in tumor site not only induces increased T cell-recruitment and elicits a specific antitumor immunity, but also mediates regression of established 4T1 tumors, indicating the potential application of ITAC-expressing tumor cells in cancer immunotherapy and vaccine designing.

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Abbreviations

ITAC:

IFN-γ-inducible T cell α chemoattractant

CXCR3:

Cys-X-Cys receptor 3

TIL:

Tumor infiltrating lymphocyte

CI:

Chemotaxis index

MMC:

Mitomycin C

CFSE:

5- and 6-carboxyfluorescein diacetate succinimydyl ester

7-AAD:

7-Amino actinomycin D

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

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Acknowledgments

We thank Prof. Hong-Ming Hu (EACRI, Portland, OR, USA) for his helpful suggestions, Yi Lin (Department of Immunology, Fudan University, Shanghai, China) for her assistance in the paper, Prof. Chong-Xian Pan (Department of Internal Medicine, UC Davis Cancer Center, USA) and Jin-Di Wen (Shanghai Medical College, Fudan University, Shanghai, China) for proofreading the paper.

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Authors and Affiliations

  1. Department of Immunology of Shanghai Medical College and Institute for Immunobiology, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, Peoples Republic of China

    Yiwei Chu, Xiuli Yang, Wei Xu, Ying Wang, Qiang Guo & Sidong Xiong

  2. Key Laboratory of Molecular Medicine of Ministry of Education, Fudan University, Shanghai, 200032, Peoples Republic of China

    Yiwei Chu, Xiuli Yang, Wei Xu, Ying Wang, Qiang Guo & Sidong Xiong

  3. Immunology Division, E-Institutes of Shanghai Universities, Shanghai, 200025, Peoples Republic of China

    Sidong Xiong

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  1. Yiwei Chu
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  2. Xiuli Yang
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  3. Wei Xu
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  4. Ying Wang
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  5. Qiang Guo
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Correspondence to Sidong Xiong.

Additional information

Grant Support: The program of Science and Technology Commission of Shanghai Municipality (STCSM) (04XD14003, 04DZ14902, 045407038), the National Natural Science Foundation of China (NSFC) (30571713) and the program for Outstanding Medical Academic Leader.

Yiwei Chu and Xiuli Yang are contributed equally to this work.

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Chu, Y., Yang, X., Xu, W. et al. In situ expression of IFN-γ-inducible T cell α chemoattractant in breast cancer mounts an enhanced specific anti-tumor immunity which leads to tumor regression. Cancer Immunol Immunother 56, 1539–1549 (2007). https://doi.org/10.1007/s00262-007-0296-1

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