期刊
CANCER IMMUNOLOGY RESEARCH
卷 3, 期 6, 页码 661-667出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-13-0226
关键词
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资金
- NIH [R01 HL 31950, HL 117807, K01-DK090416]
- MS Society [RG4981A1/T]
Inefficient T-cell homing to tissues limits adoptive T-cell immunotherapy of solid tumors. alpha L beta 2 and alpha 4 beta 1 integrins mediate trafficking of T cells into tissues via engagement of ICAM-1 and VCAM-1, respectively. Inhibiting protein kinase A (PKA)-mediated phosphorylation of alpha 4 integrin in cells results in an increase in alpha L beta 2-mediated migration on mixed ICAM-1 VCAM-1 substrates in vitro, a phenomenon termed integrin trans-regulation. Here, we created an alpha 4(S988A)-bearing mouse, which precludes PKA-mediated alpha 4 phosphorylation, to examine the effect of integrin trans-regulation in vivo. The alpha 4(S988A) mouse exhibited a dramatic and selective increase in migration of lymphocytes, but not myeloid cells, to sites of inflammation. Importantly, we found that the alpha 4(S988A) mice exhibited a marked increase in T-cell entry into and reduced growth of B16 melanomas, consistent with antitumor roles of infiltrating T cells and progrowth functions of tumor-associated macrophages. Thus, increased alpha 4 trans-regulation of alpha L beta 2 integrin function biases leukocyte emigration toward lymphocytes relative to myeloid cells and enhances tumor immunity. (C) 2015 AACR.
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