Improving CLL Vγ9Vδ2-T–cell fitness for cellular therapy by ex vivo activation and ibrutinib

Abstract

The efficacy of autologous (αβ) T-cell-based treatment strategies in chronic lymphocytic leukemia (CLL) has been modest. The Vγ9Vδ2-T cell subset consists of cytotoxic T lymphocytes with potent antilymphoma activity via a major histocompatibility complex-independent mechanism. We studied whether Vγ9Vδ2-T cells can be exploited as autologous effector lymphocytes in CLL. Healthy control Vγ9Vδ2-T cells were activated by and had potent cytolytic activity against CLL cells. However, CLL-derived Vγ9Vδ2-T cells proved dysfunctional with respect to effector cytokine production and degranulation, despite an increased frequency of the effector-type subset. Consequently, cytotoxicity against malignant B cells was hampered. A comparable dysfunctional phenotype was observed in healthy Vγ9Vδ2-T cells after coculture with CLL cells, indicating a leukemia-induced mechanism. Gene-expression profiling implicated alterations in synapse formation as a conceivable contributor to compromised Vγ9Vδ2-T-cell function in CLL patients. Dysfunction of Vγ9Vδ2-T cells was fully reversible upon activation with autologous monocyte-derived dendritic cells (moDCs). moDC activation resulted in efficient expansion and predominantly yielded Vγ9Vδ2-T cells with a memory phenotype. Furthermore, ibrutinib treatment promoted an antitumor T helper 1 (T1) phenotype in Vγ9Vδ2-T cells, and we demonstrated binding of ibrutinib to IL-2-inducible kinase (ITK) in Vγ9Vδ2-T cells. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2-T cells is fully reversible, resulting in potent cytotoxicity toward CLL cells. Our data support the potential use of Vγ9Vδ2-T cells as effector T cells in CLL immunotherapy and favor further exploration of combining Vγ9Vδ2-T-cell-based therapy with ibrutinib.

Cancer immunotherapy with γδ T cells: many paths ahead of us

“…Several studies have demonstrated that standard chemotherapeutic drugs or kinase inhibitors frequently increase the cancer cell susceptibility to γδ T cell killing, for instance, for colon cancer, 208 glioblastoma, 209 ovarian cancer, 210 or chronic lymphocytic leukemia. 211 Thus, relevant preclinical model systems suggest synergistic effects of combined chemotherapy and adoptive transfer of allogeneic Vδ2T cells. 210 A large number of substances have been shown to epigenetically modify gene expression at the level of DNA methylation and histone modification, and several drugs, including the histone deacetylase inhibitor valproic acid (VPA) and the DNA demethylating agent decitabine, are clinically used.…”

Distinct immune composition in lymph node and peripheral blood of CLL patients is reshaped during venetoclax treatment

“…The numbers of NK and CD8 1 T cells are relatively low, as well as Vd1 and Vd2 T-cell numbers, both of which have cytotoxic properties against CLL cells. 52,53 Moreover, high PD-1 expression on CD8 1 T cells fits with an immunosuppressed profile in the LN. The increased numbers of T regs in the LN that we and other investigators describe likely suppress cellular immune responses within the LN.…”

The impacts of zanubrutinib on immune cells in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

“…7 Moreover, ibrutinib has been found to help restore host immunity by increasing T cell number and repertoire diversity, improving T cell function, suppressing immunosuppressive molecule ligands such as programmed death-ligand 1 (PD-L1) on cancer cells, and eliminating BTK-expressed myeloid-derived suppressor cells (MDSC). [8][9][10][11][12][13][14] However, ibrutinib also cast negative effects on anti-tumor immunity through promotion of the anti-apoptosis effect of nurse-like cells (NLCs) and inhibition of NLC phagocytic ability by compelling them expressing M2-skewed tumor associated macrophages phenotype. 15 Besides, ibrutinib has been reported to attenuate rituximab-dependent cytotoxicity by targeting ITK in NK cells.…”