CCSG Pilot: Differential Effects of IL-10 on Anti-Tumor Immunity and Mocroenvironmental Factors in CLL

B-cell chronic lymphocytic leukemia (B-CLL) patients progressively develop an immunosuppressive state. To study the basis of this immunoregulation, we used cells from the transgenic Eì-TCL1 mouse, which spontaneously develop B-CLL due to a B-cell specific expression of the oncogene, TCL1. Eì-TCL1 CLL cells constitutively produce interleukin-10, an anti-inflammatory cytokine. Human CLL patients have more plasma IL- 10 than healthy controls. However, CLL-derived IL-10 did not affect survival of murine or human CLL cells in vitro. Here we are testing the hypothesis that IL-10 modifies CLL growth either by affecting anti-CLL specific T cell responses and/or by modifying the microenvironemtal (ME) factors. We established an adoptive transfer system consisting of transferring Eì-Tcl1 CLL cells into immunodeficient mice, where CLL cells grow rapidly. In preliminary data we also found the T cells primed with CLL cells inhibit growth of the transferred CLL cells. Moreover, IL-10R-/- CLL specific T cells are more effective in retarding CLL growth in the adoptive transfer recipients. We hypothesize that checkpoint inhibitors and chimeric antigen receptor expressing T cells are less effective in CLL than other B cell malignancies due to the inhibitory effects of IL-10. In this proposal we have three specific aims. Aim 1 will test the hypothesis that inhibition of IL-10 signaling on its own or in concert with check point inhibitors enhances the ability of T cells from mice with CLL disease to suppress growth of adoptively transferred CLL. Aim 2 will test the hypothesis that blocking IL-10 will enhance the growth of CLL in NSG mice by enhancing ME factors. We have isolated stromal cells from spleen (EMST) and bone marrow and established an in vitro flow cytometry based assay to evaluate their ability to support CLL cell proliferation, which will be utilized to further define the underlying mechanisms. Aim 3 will identify the factors that suppress T cell activation and stromal cell activation by performing gene expression analysis of stromal cells, dendritic cells and T cells treated with and without IL-10, to identify unique signaling molecules that could be targeted to enhance T cell response while suppressing ME CLL supporting factors.