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Fine-Tuning Tumor Immunity With Integrin Trans-regulation #MMPMID25600437
Cantor JM; Rose DM; Slepak M; Ginsberg MH
Cancer Immunol Res 2015[Jun]; 3 (6): 661-7 PMID25600437show ga
Inefficient T-cell homing to tissues limits adoptive T-cell immunotherapy of solid tumors. ?L?2 and ?4?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 ?4 integrin in cells results in an increase in ?L?2-mediated migration on mixed ICAM-1-VCAM-1 substrates in vitro, a phenomenon termed ?integrin trans-regulation.? Here we created an ?4(S988A)-bearing mouse, which precludes PKA-mediated ?4 phosphorylation, to examine the effect of integrin trans-regulation in vivo. The ?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 ?4(S988A) mice exhibited a marked increase in T cell entry into and reduced growth of B16 melanomas, consistent with anti-tumor roles of infiltrating T cells and pro-growth functions of tumor-associated macrophages. Thus, increased ?4 trans-regulation of ?L?2 integrin function biases leukocyte emigration towards lymphocytes relative to myeloid cells and enhances tumor immunity.