Pro-tumoral immune cell alterations in wild type and Shb-deficient mice in response to 4T1 breast carcinomas

Abstract

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.

Kinetics of immune cell responses in the multiple low‐dose streptozotocin mouse model of type 1 diabetes

“…The cross presentation by DCs play an important role to further activate T cells in autoimmune diseases and cancer . Cross‐presenting DCs can be further characterized by using a CD8α marker together with DCs markers such as CD11b and CD11c.…”

“…The cross presentation by DCs play an important role to further activate T cells in autoimmune diseases 37,38 and cancer. 39,40 Cross-presenting DCs can be further characterized Vehicle MLDSTZ by using a CD8α marker together with DCs markers such as CD11b and CD11c. Therefore, we examined the proportion of CD11b + CD11c − CD8 + , CD11b − CD11c + CD8 + , and CD11b + CD11c + CD8 + DCs.…”

Cellular immunological changes in patients with LADA are a mixture of those seen in patients with type 1 and type 2 diabetes

“…This cytokine is a novel anti‐inflammatory cytokine, which belongs to the IL‐12 cytokine family, and has two subunits, Ebi3 and IL‐12p35 . It has previously been reported that IL‐35 suppresses autoimmunity and plays a putative role in tumour biology . We have found that the systemic administration of IL‐35 prevented the development of autoimmune diabetes in the multiple low‐dose streptozotocin (MLDSTZ) mouse model, and effectively reversed established disease in both the MLDSTZ and non‐obese diabetic mouse models of T1D by maintaining the normal suppressive phenotype of T reg cells .…”

The Cdh5-CreERT2 transgene causes conditional Shb gene deletion in hematopoietic cells with consequences for immune cell responses to tumors

“…Thymi, spleens, inguinal lymph nodes, bone marrows and blood were collected and cells isolated that were stained for CD4 and FoxP3 and analyzed by fluorescence activated cell sorting (FACS) as described 5 .…”