Using gamma‐cytokine complexes to improve antigen specific CD8 T cell responses in tumor‐bearing mice

Abstract

In the absence of inflammatory signals, the exposure of T cells to tumor antigen in the periphery results in tolerance. Remaining tumor specific T cells are usually of low avidity or anergic. Immunotherapy aims at reversing this tolerance to induce an efficient T cell response. STAT5 Cytokines of the interleukin‐2 family signal through STAT5 and are candidates to increase T cell anti‐tumor response. The effects of these cytokines are greatly increased when the cytokine is complexed with a specific antibody.We have studied the potential of cytokine complexes to serve as adjuvants for CD8 cells activation in a murine model, RIP‐Tag2‐HA, in which pancreatic insulomas expressing the influenza hemagglutinin (HA) as a surrogate antigen develop spontaneously. HA specific CD8 cells become effector after 3 days of treatment with IL‐2 complexes and antigen in vivo. This differentiation leads to the elimination of endogenous tumors by high avidity HA specific CD8 cells. Survival of CD8 cells is increased by using the TLR ligands polyIC or by extending the length of treatment with IL‐2 complexes. Under such conditions, even low avidity HA specific CD8 cells eliminate the tumors. We further show that cytokine complexes also increase survival of adoptively transferred, ex‐vivo activated HA specific CD8 cells. These results indicate that IL‐2 complexes are strong adjuvants that greatly enhance tumor vaccines or immunotherapy.