Abstract 2965: Myeloid depletion reverses established T-ALL growth in vivo

Abstract

Abstract T cell acute lymphoblastic leukemia (T-ALL) is a hematological cancer that arises from developing T-cells. Most T-ALL research has focused on elucidating cell-intrinsic genetic permutations that promote tumor proliferation and survival, which has resulted in a detailed description and understanding of the genetic mutations associated with T-ALL in patient cells. However, to date these studies have not resulted in effective targeted therapies, which may potentially be due to the heterogeneity of genetic lesions within and between patients or the acquisition of new mutations. Thus, we need to broaden our understanding of other factors promoting T-ALL growth to identify alternative therapeutic targets that are effective across mutational landscapes. To this end, our studies seek to identify extrinsic signals in the tumor microenvironment that enable T-ALL growth. Our previous studies used a systematic and unbiased evaluation of endogenous stromal subsets from the thymic TME to reveal that myeloid cells, primarily dendritic cells (DC), were necessary and sufficient for ex vivo survival of T-ALL cells. Furthermore, transcriptional profiling revealed elevated expression of Igf1r and Igf1 by T-ALL and DC from the TME, respectively. Using multiple molecular approaches, inhibition of IGF1R revealed that IGF1R signaling was necessary for DC-mediated survival of T-ALL from multiple tumor locations. These findings have relevance to human T-ALL as pervasive TEC-free regions containing extensive DC networks were evident in T-ALL patient samples, and previous studies have verified that IGF1R, a direct target of NOTCH1, is expressed at high levels in T-ALL patients. In these studies, we sought to determine whether myeloid cells were required for tumor survival in vivo. After transplantation, tumors became established systemically in lymphoid and non-lymphoid tissues of the recipients. Immunofluorescence analysis revealed extensive myeloid networks around and between T-ALL tumor cells in multiple tissues. As for primary tumors, transplanted T-ALL cells also required the presence of DC from the TME for survival ex vivo. Importantly, myeloid cell depletion in transplanted hosts with established T-ALL resulted in substantial reduction in tumor cell burden in all tissues examined, thus demonstrating a fundamental role for these cells in supporting T-ALL in vivo. To identify key survival pathways activated in T-ALL cells by myeloid cells, we have compared comprehensive trancscriptomic and phosphoproteomic profiling from tumor cells in the presence or absence of myeloid cells in transplant models. Preliminary analysis of T-ALL versus WT thymocytes has confirmed hyper-activated IGF1R signaling, as indicated by hyper-phosphorylation of downstream targets, such as IRS1. Collectively, these studies provide the first evidence that myeloid cells directly support T-ALL in vivo, suggesting that these cells and their associated signals may be auspicious therapeutic targets. Citation Format: Todd A. Triplett, Aram Lyu, Wesley Godfrey, Lauren I.E. Ehrlich. Myeloid depletion reverses established T-ALL growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2965. doi:10.1158/1538-7445.AM2017-2965