Fine-tuning Tumor Immunity with Integrin Trans-regulation

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.