To understand the efficacy of the tyrosine kinase inhibitors (TKIs) imatinib and nilotinib in cancer therapy, Bellora et al. explored their effects on immune cell subsets. Reduced monocyte viability, alteration in the chemokine receptor repertoires on NKs, and limited functional effects on NKs and macrophages suggest a tumor microenvironment tipped toward anti-tumor immunity.
Tyrosine kinase inhibitors (TKIs) are used in the clinical management of hematological neoplasms. Moreover, in solid tumors such as stage 4 neuroblastomas (NB), imatinib showed benefits that might depend on both on-target and immunological off-target effects. We investigated the effects of imatinib and nilotinib on human NK cells, monocytes, and macrophages. High numbers of monocytes died upon exposure to TKI concentrations similar to those achieved in patients. Conversely, NK cells were highly resistant to the TKI cytotoxic effect, were properly activated by immunostimulatory cytokines, and degranulated in the presence of NB cells. In NB, neither drug reduced the expression of ligands for activating NK receptors or upregulated that of HLA class I, B7-H3, PD-L1, and PD-L2, molecules that might limit NK cell function. Interestingly, TKIs modulated the chemokine receptor repertoire of immune cells. Acting at the transcriptional level, they increased the surface expression of CXCR4, an effect observed also in NK cells and monocytes of patients receiving imatinib for chronic myeloid leukemia. Moreover, TKIs reduced the expression of CXCR3 (in NK cells) and CCR1 (in monocytes). Monocytes also decreased the expression of M-CSFR, and low numbers of cells underwent differentiation toward macrophages. M0 and M2 macrophages were highly resistant to TKIs and maintained their phenotypic and functional characteristics. Importantly, also in the presence of TKIs, the M2 immunosuppressive polarization was reverted by TLR engagement, and M1-oriented macrophages fully activated autologous NK cells. Our results contribute to better interpreting the off-target efficacy of TKIs in tumors and to envisaging strategies aimed at facilitating antitumor immune responses.
Author Info: (1) Dipartimento di Medicina Sperimentale, Universita degli Studi di Genova, 16132 Genoa, Italy. (2) Dipartimento di Medicina Sperimentale, Universita degli Studi di Genova, 16132
Author Info: (1) Dipartimento di Medicina Sperimentale, Universita degli Studi di Genova, 16132 Genoa, Italy. (2) Dipartimento di Medicina Sperimentale, Universita degli Studi di Genova, 16132 Genoa, Italy. (3) Istituto Giannina Gaslini, 16148 Genoa, Italy. (4) Dipartimento di Medicina Sperimentale, Universita degli Studi di Genova, 16132 Genoa, Italy. (5) Istituto Giannina Gaslini, 16148 Genoa, Italy. (6) Dipartimento di Medicina Sperimentale, Universita degli Studi di Genova, 16132 Genoa, Italy. (7) Dipartimento di Medicina Sperimentale, Universita degli Studi di Genova, 16132 Genoa, Italy; alemoret@unige.it. Centro di Eccellenza per la Ricerca Biomedica, Universita degli Studi di Genova, 16132 Genoa, Italy. (8) Dipartimento di Medicina Molecolare, Universita di Pavia, 27100 Pavia, Italy. Dipartimento di Onco-Ematologia, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy; and. (9) Dipartimento di Medicina Molecolare, Universita di Pavia, 27100 Pavia, Italy. (10) Dipartimento di Onco-Ematologia Pediatrica, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesu, 00146 Rome, Italy. (11) Dipartimento di Medicina Molecolare, Universita di Pavia, 27100 Pavia, Italy. Dipartimento di Onco-Ematologia Pediatrica, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesu, 00146 Rome, Italy. (12) Dipartimento di Medicina Sperimentale, Universita degli Studi di Genova, 16132 Genoa, Italy. Istituto Giannina Gaslini, 16148 Genoa, Italy. (13) Dipartimento di Medicina Sperimentale, Universita degli Studi di Genova, 16132 Genoa, Italy. Centro di Eccellenza per la Ricerca Biomedica, Universita degli Studi di Genova, 16132 Genoa, Italy.
