Pro-tumoral immune cell alterations in wild type and Shb-deficient mice in response to 4T1 breast carcinomas
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Xiujuan Li1,3, Kailash Singh1, Zhengkang Luo1, Mariela Mejia-Cordova1, Maria Jamalpour1, Björn Lindahl1, Ganlin Zhang2, Stellan Sandler1 and Michael Welsh1
1Department of Medical Cell Biology, Uppsala University, Uppsala 75123, Sweden
2Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala 75123, Sweden
3Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
Michael Welsh email: [email protected]
Xiujuan Li, email: [email protected]
Keywords: breast cancer; metastasis; angiogenesis; innate immunity; regulatory T cells
Received: August 29, 2017 Accepted: February 21, 2018 Published: April 10, 2018
To assess mechanisms responsible for breast carcinoma metastasis, 4T1 breast carcinomas were grown orthotopically in wild type or Shb knockout mice. Tumor growth, metastasis, vascular characteristics and immune cell properties were analyzed. Absence of Shb did not affect tumor growth although it increased lung metastasis. Shb knockout mouse tumors showed decreased redness and less developed vascular plexa located at the periphery of the tumors. No difference in overall tumor vascular density, leakage or pericyte coverage was noted between the genotypes although the average vessel size was smaller in the knockout. Tumors induced an increase of CD11b+ cells in spleen, lymph node, thymus, bone marrow and blood. Numbers of Shb knockout CD11b/CD8+ cells were decreased in lymph nodes and bone marrow of tumor bearing mice. Mice with tumors had reduced numbers of CD4+ lymphocytes in blood/lymphoid organs, whereas in most of these locations the proportion of CD4+ cells co-expressing FoxP3 was increased, suggesting a relative increase in Treg cells. This finding was reinforced by increased blood interleukin-35 (IL-35) in wild type tumor bearing mice. Shb knockout blood showed in addition an increased proportion of IL-35 expressing Treg cells, supporting the notion that absence of Shb further promotes tumor evasion from immune cell recognition. This could explain the increased number of lung metastases observed under these conditions. In conclusion, 4T1 tumors alter immune cell responses that promote tumor expansion, metastasis and escape from T cell recognition in an Shb dependent manner.
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