Session: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster III
Hematology Disease Topics & Pathways:
Leukemia, Biological, Diseases, CLL, Therapies, enzyme inhibitors, Biological Processes, Lymphoid Malignancies, immune mechanism, microenvironment
In search for an explanation for this failure, we investigated genes that are induced upon resistance to immune checkpoint blockade and identified the phenylalanine-catabolizing enzyme interleukin-4-induced 1 (IL4I1). IL4I1 is strongly expressed in cancer-associated myeloid cells as well as tumor cells of different entities, including CLL and other B cell lymphoma, and was attributed immunosuppressive functions. We thus explored its role in cancer immune escape in bone marrow-chimeric mice that lack IL4I1 in the hematopoietic tumor microenvironment. Adoptive transfer of Eµ-TCL1 leukemia in these mice showed that lack of IL4I1 in hematopoietic cells resulted in a dramatically reduced tumor development compared to respective control mice (Figure 1A). In-depth analysis of the immune compartment of these mice by flow cytometry and transcriptome analyses revealed that IL4I1 deficiency was associated with lower expression of immune checkpoint molecules including PD-1 on CD8 T cells. Moreover, CD8+ effector T cells of IL4I1-deficient mice were highly enriched in a transcriptional signature of genes that was downregulated upon T-cell exhaustion (Figure 1B). We further observed less suppressive regulatory T cells, and enhanced antigen presentation capacity of dendritic cells in the IL4I1-deficient chimeric mice developing CLL. Altogether, these results provide evidence for a central role for IL4I1 in CLL-associated immune suppression and suggest IL4I1 as attractive novel target for immunotherapy of cancer, including tumors that do not respond to IDO1 inhibitors.
Figure 1: CLL development and CD8 T cell phenotype in mice with IL4I1-deficient microenvironment
A: Bone marrow (BM)-chimeric mice were generated by i.v. transplantation of 5 x 106 BM cells of wildtype (WT) or Il4i1-/- mice in lethally irradiated C57BL/6 mice. After reconstitution of the hematopoietic system, 10 weeks after BM transfer, mice were i.v. transplanted with 1 x 107 malignant B cells of Eµ-TCL1 mice and CLL development was monitored in peripheral blood over time by quantifying absolute number of CD5+ CD19+ CLL cells by flow cytometry. B: 5 weeks after CLL cell transfer, mice were sacrificed and splenic CD8+ effector T cells were sorted for transcriptome analysis by microarrays. Gene set enrichment analysis of ranked-list of genes (fold change) was performed using published signatures which showed an enrichment of genes that are downregulated in exhausted versus memory CD8+ T cells in Il4i1-/- in comparison to WT mice.
Disclosures: No relevant conflicts of interest to declare.
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