[PubMed] [Google Scholar] 46. T-cell activation, chemokine manifestation, motility and lytic synapses with CLL cells, as well as IFN-inducible opinions inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments that responded to anti-PD-L1/PD-1-based combination therapy. Notably, medical analyses showed improved PD-L1 manifestation on T cells, as well as LYN-1604 hydrochloride intratumoral manifestation of chemokine signaling genes in B-cell malignancy individuals receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy. Visual Abstract Open in a separate window Introduction Defense checkpoint blockade offers shown that reinvigorating anti-tumor immune activity can induce durable reactions across multiple malignancy types.1-3 Anti-programmed death 1 (PD-1) is expressed by T cells following activation and remains about exhausted T cells within a chronic inflammatory environment. PD-1 transmits inhibitory signals into T cells in the immunological synapse following engagement with its ligands anti-PD-1 ligand (PD-L1) or PD-L2 indicated on tumor cells or antigen-presenting cells.4 Constitutive expression of PD-1 ligands through genomic amplification is seen in Hodgkin lymphoma (HL).5 In addition, pro-inflammatory cytokines including interferon- (IFN-) contribute to PD-L1 expression in the tumor microenvironment (TME).2 Blocking the connection of PD-1 with its ligands helps prevent inhibitory signaling and allows tumor-specific T cells to remain activated against tumor cells. Probably the most encouraging clinical reactions to PD-1 blockade have been seen in HL.5,6 However, the effectiveness of anti-PD-1 immunotherapy in non-HLs (NHLs) including diffuse large B-cell lymphoma (DLBCL) has been more modest.7 Unexpectedly, no activity was seen in a trial of anti-PD-1 therapy for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL),8 even although PD-L1-PD-1-mediated T-cell dysfunction has been explained.9-11 This clinical encounter suggests that profound immunosuppressive barriers operate within the TME. Clinical activity of checkpoint inhibitors in malignancy has been correlated with reduced disease burden,12 strong PD-L1 manifestation in the TME,5,13,14 tumor neoantigen weight,15 and mutations in antigen demonstration and IFN- pathways.16-18 Additional studies possess implicated T-cell state, including the quantity of tumor-infiltrating cytotoxic CD8+ T cells19 and IFN- response immune signatures.20,21 Strong expression of PD-L1 is thought to reflect active anti-tumor T-cell activity and represent a marker of adaptive IFN-inducible immune resistance,19 that characterizes T cell-inflamed microenvironments.22 However, studies suggest that PD-L1 manifestation in the CLL TME is relatively low.8,10,23,24 Furthermore, although CLL cells are capable of responding to IFN- and their major histocompatibility LYN-1604 hydrochloride complex molecules are intact,9,25 a low frequency of neoantigen generation26,27 likely fosters poor tumor immunogenicity. In addition, CLL cells communicate low levels of adhesion and costimulatory molecules required for effective immune acknowledgement.28,29 T-cell dysfunction in CLL has been linked to tumor-induced cytoskeletal reprogramming,30 and a defective ability to migrate31,32 and form immune synapses.9,29,33 Thus, NESP identifying effective therapies capable of reestablishing immune effector functions could offer hope for R/R patients, as well as deepen targeted agent-induced responses.34 Avadomide (CC-122) is a cereblon E3 ligase modulator (CELMoD) drug that has demonstrated clinical activity in DLBCL.35 Avadomide, like the immunomodulatory drug lenalidomide, binds to the protein target cereblon, a substrate receptor in the cullin4 E3 ligase complex, that encourages recruitment, LYN-1604 hydrochloride ubiquitination, and subsequent proteasomal degradation of the hematopoietic transcription factors Aiolos and Ikaros.36,37 Mechanistically, avadomide causes an IFN response in DLBCL cells that induces direct tumor apoptosis.38 In contrast, avadomide is not directly cytotoxic to CLL cells, but has been reported to possess anti-proliferative activity.39 Advantageously, degradation of Aiolos and Ikaros in T cells by CELMoDs derepresses interleukin-2 (IL-2) transcription and production, leading to activation.38,40 The ability of avadomide to directly inhibit tumor cells while revitalizing immune cells, suggests that it could represent a complementary treatment partner for checkpoint blockers. Here, we demonstrate that avadomide induces type I and II IFN signaling in previously worn out patient T cells using CLL like a model B-cell malignancy. Our studies reveal that the ability of this immunomodulatory drug to activate this immune compartment causes a potent cascade reaction, that pairs efficiently with PD-L1/-PD-1 axis blockade, leading to enhanced T cell-mediated CLL killing. Methods Patient samples All patient- and age-matched healthy samples were acquired after written.
