Supplemental Figure 1. Generation of the α4(S998A) mouse. Supplemental Figure 2. (A) Hematological analysis. B) Na?ve lymphoid organ lymphocyte subsets. C) Humoral immune response. Supplemental Figure 3. Intrinsic homing advantage of α4(S998A) splenocytes. Supplemental Figure 4. Migration of α4(S998A lymphocytes in vitro. Supplemental Figure 5. Lewis Lung Carcinoma Tumor Growth. Supplemental Figure 6. Tumor growth after depletion of lymphoid cells in α4(S988A) mice. Supplemental Figure 7. Migration of α4(S998A) macrophages.
ARTICLE ABSTRACT
Inefficient T-cell homing to tissues limits adoptive T-cell immunotherapy of solid tumors. αLβ2 and α4β1 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 α4 integrin in cells results in an increase in αLβ2-mediated migration on mixed ICAM-1–VCAM-1 substrates in vitro, a phenomenon termed “integrin trans-regulation.” Here, we created an α4(S988A)-bearing mouse, which precludes PKA-mediated α4 phosphorylation, to examine the effect of integrin trans-regulation in vivo. The α4(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 α4(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 α4 trans-regulation of αLβ2 integrin function biases leukocyte emigration toward lymphocytes relative to myeloid cells and enhances tumor immunity. Cancer Immunol Res; 3(6); 661–7. ©2015 AACR.
