Abstract
The central tumoricidal activity of anticancer monoclonal antibodies (mAb) is exerted by FcγR IIIa (CD16)-expressing effector cells in vivo via antibody-dependent cell-mediated cytotoxicity (ADCC), as observed for natural killer (NK) cells. In practice, chemotherapy-induced leukopenia and exhaustion of NK cells resulting from ADCC often hamper the clinical efficacy of cancer treatment. To circumvent this drawback, we examined in vivo the feasibility of T cells, gene-modified to express a newly generated affinity-matured (158V/V) chimeric CD16-CD3ζ receptor (cCD16ζ-T cells), as a transferable alternative effector for cancer mAb therapy. cCD16ζ-T cells were readily expandable in ex vivo culture using anti-CD2/CD3/CD28 beads and recombinant human interleukin-2 (rhIL-2), and they successfully displayed ADCC-mediated tumoricidal activity in vitro. During ADCC, ligation of opsonized cancer cells to the introduced cCD16ζ-T cells stimulated the effector cells to produce proinflammatory cytokines and release toxic granules through the activation of the Nuclear factor of activated T cells (NFAT) pathway after phosphorylation of the CD3ζ chain. In parallel, these stimulated cCD16ζ-T cells transiently proliferated and differentiated into effector memory T cells. In contrast, NK cells activated by rhIL-2 displayed similar ADCC activity, but failed to proliferate. Human cCD16ζ-T cells infused concomitantly with anti-CD20 mAb synergistically inhibited the growth of disseminated Raji cells, a CD20(+) lymphoma cell line, in immunodeficient mice, whereas similarly infused rhIL-2-treated NK cells survived for a shorter time and displayed less effective tumor suppression. Our findings strongly suggest the clinical feasibility of cCD16ζ-T cells as adoptively transferable ADCC effector cells that could potentially enhance the clinical responses mediated by currently available anticancer mAbs.
Highlights
Monoclonal antibodies specific for tumor antigens are efficacious in the treatment of cancers [1]; these include anti-CD20 mAb for CD20þ lymphoid malignancies [2] and anti-Her2/Neu mAb for Her2/Neuþ solid tumors [3]
CD3z phosphorylated at 142Y tended, without statistical significance, to increase in cCD16z-Jurkat/MA/CD8a/luc cells ligated with opsonized CD20þ Raji cells in the presence of 1 mg/mL of rituximab (MFI 1⁄4 8.34 Æ 3.4, mean Æ SE), but not in cCD16z-Jurkat/MA/CD8a/ luc cells ligated with Raji cells alone (MFI 1⁄4 3.23 Æ 1.4, mean Æ SE), 1 mg/mL of rituximab alone (MFI 1⁄4 3.15 Æ 1.6, mean Æ SE), or treated K562 cells as a control with 1 mg/mL of rituximab (MFI 1⁄4 3.58 Æ 1.4, mean Æ SE; Fig. 1C)
A decline in the clinical efficacy of this treatment is often observed, and this involves both chemotherapy-induced leukopenia and natural killer (NK) cell exhaustion due to antibody-dependent cell-mediated cytotoxicity (ADCC) evoked by the applied mAb [5]
Summary
Monoclonal antibodies (mAb) specific for tumor antigens are efficacious in the treatment of cancers [1]; these include anti-CD20 mAb (rituximab) for CD20þ lymphoid malignancies [2] and anti-Her2/Neu mAb (trastuzumab) for Her2/Neuþ solid tumors [3]. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/). As anticancer treatment proceeds, a decline in the clinical efficacy of the mAb therapy is often observed. This decline in efficacy could be attributed to the decrease in the number of active effector cells during the ADCC process from a combination of chemotherapy-induced leukopenia and NK cell exhaustion [5]. As CD16-expressing effector cells play a critical role in ADCC, we hypothesized that the combined therapeutic regimen of replenishing these cells together with the specific anticancer mAb may improve cancer treatment
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