Editors' ChoiceCancer

Increasing Imatinib Efficacy with Immunotherapy

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Science Signaling  20 Sep 2011:
Vol. 4, Issue 191, pp. ec261
DOI: 10.1126/scisignal.4191ec261

Imatinib mesylate (imatinib, also known as Gleevec) is an effective therapy for about 80% of patients with advanced gastrointestinal stromal tumor (GIST). Because most GISTs contain activating mutations in the receptor tyrosine kinase Kit, these therapeutic effects have been attributed to imatinib’s inhibition of Kit-driven signals within tumor cells. Using transgenic GIST mice heterozygous for a gene encoding an activated form of Kit (KitV558/+), Balachandran et al. found that imatinib’s efficacy not only was due to its ability to inhibit Kit but also required its ability to alleviate local immunosuppression. Imatinib treatment, but not treatment with vehicle alone, induced an increase in the number, activation (abundance of CD69), and cytolytic capacity (abundance of granzyme B) of CD8+ T cells within GISTs, whereas it decreased, through apoptosis, the number of intratumoral regulatory T (Treg) cells. Moreover, the ability of imatinib to reduce tumor weight and volume was lessened, but not completely abolished, in GIST mice depleted of CD8+ T cells through intraperitoneal injections of a CD8-specific antibody. The enzyme indoleamine 2,3-dioxygenase (Ido) metabolizes tryptophan into molecules that stimulate the immunosuppressive potential of Treg cells, and Ido mRNA and protein amounts were lower in tumors derived from imatinib-treated versus vehicle-treated GIST mice. Furthermore, pharmacological inhibition of Ido had therapeutic effects similar to those of treatment of GISTs with imatinab. Conversely, treatment of GIST mice with imatinib plus immunosuppressive tryptophan metabolites diminished imatinib’s ability to reduce tumor weight. Similar to the tumors of GIST mice, imatinib-sensitive human GIST samples also contained an increased ratio of intratumoral CD8+ T cells to Treg cells compared with that in imatinib-resistant or untreated GISTs. Finally, imatinib treatment together with antibody-mediated blockade of CTLA-4 (cytotoxic T lymphocyte–associated antigen 4), which can lead to an accumulation of effector cytokine-producing CD8+ T cells, was more effective in reducing the volume of mouse GISTs than either treatment alone. Together, the results suggest that combining anticancer drugs with immunotherapy may provide a better overall treatment for some types of cancer (see also commentary by Zitvogel and Kroemer).

V. P. Balachandran, M. J. Cavnar, S. Zeng, Z. M. Bamboat, L. M. Ocuin, H. Obaid, E. C. Sorenson, R. Popow, C. Ariyan, F. Rossi, P. Besmer, T. Guo, C. R. Antonescu, T. Taguchi, J. Yuan, J. D. Wolchok, J. P. Allison, R. P. DeMatteo, Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat. Med. 17, 1094–1100 (2011). [PubMed]

L. Zitvogel, G. Kroemer, Anticancer effects of imatinib via immunostimulation. Nat. Med. 17, 1050–1051 (2011). [PubMed]

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