1. Figure 2 Effects of imatinib on components of the anticancer immunosurveillance system
Figure 2 | Effects of imatinib on components of the anticancer immunosurveillance system. The on-target effect of imatinib on oncogenic protein tyrosine kinases (PTKs) is accompanied by decreased expression of indoleamine 2,3-dioxygenase (IDO), reduced kynurenin secretion, and the subsequent apoptosis of regulatory T (TREG) cells and relative expansion of cytotoxic T-cell lymphocytes (CTL), as well as by reduced secretion of VEGF and subsequent antiangiogenic effects. This direct effect of imatinib also reduces NKG2D ligand expression on neoplastic cells, thereby compromising their recognition by NKG2D-expressing natural killer (NK) cells (upper left panel). Myeloid-derived suppressor cell (MDSC) populations in patients with chronic myeloid leukaemia (CML) at diagnosis, which can be derived from the tumour clone bearing the BCR–ABL1 fusion gene, are normalized following imatinib therapy or as a result of reduced VEGF serum concentrations (upper panels). The imatinib-induced reprogramming of tumour-associated macrophages (TAMs) to an M2 phenotype is an 'on target' process, which involves TAM interaction with apoptotic tumour cells (right upper panel). By targeting KIT on dendritic cells (DCs), imatinib reduces spontaneous and FLT3L-induced DC differentiation, but permits DC–NK cell crosstalk in lymph nodes and the spleen (lower left panel). Imatinib targets ABL1 and ABL2, as well as LCK, which are involved in T-cell development and the function of mature T cells, contributing to decreased T-cell receptor (TCR)-mediated T-cell proliferation and activation in vitro and blunted delayed-type hypersensitivity in vivo (lower right panel). The off-target inhibition of Bruton tyrosine kinase (BTK) by imatinib induces reductions in IgM-expressing memory-B-cell frequency, hypogammaglobulinaemia, and impaired humoural responses to vaccines. Imatinib can, however, also promote expansion of a specific bone marrow subset of CD20+CD5+sIgM+ B lymphocytes, inducing higher plasma levels of IgM specific for O-linked sugars expressed by leukaemic cells (lower right panel).
Kroemer, G. et al. (2016) Immunological off-target effects of imatinib
Nat. Rev. Clin. Oncol. doi: /nrclinonc