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Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido.

Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, Sorenson EC, Popow R, Ariyan C, Rossi F, Besmer P, Guo T, Antonescu CR, Taguchi T, Yuan J, Wolchok JD, Allison JP, DeMatteo RP - Nat. Med. (2011)

Bottom Line: The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor-cell survival and proliferation.Imatinib therapy activated CD8(+) T cells and induced regulatory T cell (T(reg) cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido).Thus, T cells are crucial to the antitumor effects of imatinib in GIST, and concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Memorial Hospital, New York, New York, USA.

ABSTRACT
Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and produces a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor-cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the antitumor effects of imatinib. Imatinib therapy activated CD8(+) T cells and induced regulatory T cell (T(reg) cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are crucial to the antitumor effects of imatinib in GIST, and concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents.

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CTLA-4 blockade is synergistic with imatinibGIST mice were treated with imatinib or vehicle for 7 d with or without induction CTLA-4 blockade or isotype control antibody followed by chronic CTLA-4 blockade. (a) Tumor size was monitored using serial MRIs. (b–e) Tumors and DLNs of GIST mice were analyzed on days 16–18 to determine (b) frequency and absolute number of CD4+ and CD8+ T cells in DLN, (c) frequency of intratumoral CD4+ and CD8+ T cells, and (d) intratumoral CD8+ T cell to T reg ratio. (e) Intratumoral CD8+ T cells were stimulated for 4 h with phorbol 12-myristate 13-acetate and ionomycin followed by intracellular analysis for IFN-γ production; P = 0.09, two-tailed student t-test. Data in (a) represent means ± s.e.m. of a composite of two independent experiments each with 3–5 mice per group. Data in (b–e) represent means ± s.e.m. with n = 6–8 per group. *P < 0.05.
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Figure 6: CTLA-4 blockade is synergistic with imatinibGIST mice were treated with imatinib or vehicle for 7 d with or without induction CTLA-4 blockade or isotype control antibody followed by chronic CTLA-4 blockade. (a) Tumor size was monitored using serial MRIs. (b–e) Tumors and DLNs of GIST mice were analyzed on days 16–18 to determine (b) frequency and absolute number of CD4+ and CD8+ T cells in DLN, (c) frequency of intratumoral CD4+ and CD8+ T cells, and (d) intratumoral CD8+ T cell to T reg ratio. (e) Intratumoral CD8+ T cells were stimulated for 4 h with phorbol 12-myristate 13-acetate and ionomycin followed by intracellular analysis for IFN-γ production; P = 0.09, two-tailed student t-test. Data in (a) represent means ± s.e.m. of a composite of two independent experiments each with 3–5 mice per group. Data in (b–e) represent means ± s.e.m. with n = 6–8 per group. *P < 0.05.

Mentions: Concurrent administration of imatinib and induction treatment with CTLA-4 specific blocking antibody for 1 week followed by chronic CTLA-4 blockade significantly decreased tumor size in established mouse GISTs compared with either treatment alone (Fig. 6a, Supplementary Figure 8). It has been shown that CTLA-4 blockade during priming can lead to accumulation of CD8+ T cells capable of producing effector cytokines such as IFN-γ.31 GIST mice treated with imatinib and CTLA-4 blockade demonstrated no change in the frequency or absolute number of CD4+ or CD8+ T cells in DLN or tumor (Fig. 6b, c), or the CD8+ T effector to T reg ratio in the tumor (Fig. 6d). Intratumoral CD8+ T cells demonstrated a trend of enhanced IFN-γ production (Fig. 6e). Therefore, combined therapy of imatinib and CTLA-4 blockade has potential therapeutic promise for human GIST and may exert anti-tumor effects by increasing IFN-γ producing CD8+ T cells.


Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido.

Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, Sorenson EC, Popow R, Ariyan C, Rossi F, Besmer P, Guo T, Antonescu CR, Taguchi T, Yuan J, Wolchok JD, Allison JP, DeMatteo RP - Nat. Med. (2011)

CTLA-4 blockade is synergistic with imatinibGIST mice were treated with imatinib or vehicle for 7 d with or without induction CTLA-4 blockade or isotype control antibody followed by chronic CTLA-4 blockade. (a) Tumor size was monitored using serial MRIs. (b–e) Tumors and DLNs of GIST mice were analyzed on days 16–18 to determine (b) frequency and absolute number of CD4+ and CD8+ T cells in DLN, (c) frequency of intratumoral CD4+ and CD8+ T cells, and (d) intratumoral CD8+ T cell to T reg ratio. (e) Intratumoral CD8+ T cells were stimulated for 4 h with phorbol 12-myristate 13-acetate and ionomycin followed by intracellular analysis for IFN-γ production; P = 0.09, two-tailed student t-test. Data in (a) represent means ± s.e.m. of a composite of two independent experiments each with 3–5 mice per group. Data in (b–e) represent means ± s.e.m. with n = 6–8 per group. *P < 0.05.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3278279&req=5

Figure 6: CTLA-4 blockade is synergistic with imatinibGIST mice were treated with imatinib or vehicle for 7 d with or without induction CTLA-4 blockade or isotype control antibody followed by chronic CTLA-4 blockade. (a) Tumor size was monitored using serial MRIs. (b–e) Tumors and DLNs of GIST mice were analyzed on days 16–18 to determine (b) frequency and absolute number of CD4+ and CD8+ T cells in DLN, (c) frequency of intratumoral CD4+ and CD8+ T cells, and (d) intratumoral CD8+ T cell to T reg ratio. (e) Intratumoral CD8+ T cells were stimulated for 4 h with phorbol 12-myristate 13-acetate and ionomycin followed by intracellular analysis for IFN-γ production; P = 0.09, two-tailed student t-test. Data in (a) represent means ± s.e.m. of a composite of two independent experiments each with 3–5 mice per group. Data in (b–e) represent means ± s.e.m. with n = 6–8 per group. *P < 0.05.
Mentions: Concurrent administration of imatinib and induction treatment with CTLA-4 specific blocking antibody for 1 week followed by chronic CTLA-4 blockade significantly decreased tumor size in established mouse GISTs compared with either treatment alone (Fig. 6a, Supplementary Figure 8). It has been shown that CTLA-4 blockade during priming can lead to accumulation of CD8+ T cells capable of producing effector cytokines such as IFN-γ.31 GIST mice treated with imatinib and CTLA-4 blockade demonstrated no change in the frequency or absolute number of CD4+ or CD8+ T cells in DLN or tumor (Fig. 6b, c), or the CD8+ T effector to T reg ratio in the tumor (Fig. 6d). Intratumoral CD8+ T cells demonstrated a trend of enhanced IFN-γ production (Fig. 6e). Therefore, combined therapy of imatinib and CTLA-4 blockade has potential therapeutic promise for human GIST and may exert anti-tumor effects by increasing IFN-γ producing CD8+ T cells.

Bottom Line: The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor-cell survival and proliferation.Imatinib therapy activated CD8(+) T cells and induced regulatory T cell (T(reg) cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido).Thus, T cells are crucial to the antitumor effects of imatinib in GIST, and concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Memorial Hospital, New York, New York, USA.

ABSTRACT
Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and produces a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor-cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the antitumor effects of imatinib. Imatinib therapy activated CD8(+) T cells and induced regulatory T cell (T(reg) cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are crucial to the antitumor effects of imatinib in GIST, and concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents.

Show MeSH
Related in: MedlinePlus