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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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Imatinib alters intratumoral T cells through inhibition of Ido(a) Ido mRNA in the DLN and tumor as determined by microarray analysis of vehicle treated GIST mice and the tumor from imatinib treated GIST mice after 7 days (left panel, n = 3 per group). Western blot (WB) staining for Ido in the DLN, spleen (center panel, left half), and tumor of vehicle treated GIST mice and tumor of imatinib treated GIST mice (center panel, right half). Intracellular Ido expression in CD45+ intratumoral immune cells and CD45−Kit+ tumor cells as determined by flow cytometry (right panel). (b) Tumor weight of GIST mice treated with 1-MT for 7 d with or without CD8+ T cell depletion. (c–i) GIST mice were treated for 7 d with combinations of 1-MT or control (Ctrl), imatinib (I), or vehicle (V), and tryptophan metabolites (metabs). Tumors and DLNs were analyzed using flow cytometry. (c) Frequency of intratumoral CD8+Ki67+ and CD8+CD69+ T cells. (d) Frequency of intratumoral Annexin V+ T regs. (e) Intratumoral CD8+ T cell to T reg ratio. (f) Tumor weight. (g) MFI and frequency of intratumoral CD8+CD69+ and CD8+granzyme B+ T cells. (h) Frequency of intratumoral Annexin V+ T regs. (i) Intratumoral CD8+ T cell to T reg ratio. Data in (a) left panel represent means ± s.e.m. and are shown relative to internal controls (housekeeping gene). Data represent means ± s.e.m. with n = 6–12 per group. *P < 0.05.
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Figure 3: Imatinib alters intratumoral T cells through inhibition of Ido(a) Ido mRNA in the DLN and tumor as determined by microarray analysis of vehicle treated GIST mice and the tumor from imatinib treated GIST mice after 7 days (left panel, n = 3 per group). Western blot (WB) staining for Ido in the DLN, spleen (center panel, left half), and tumor of vehicle treated GIST mice and tumor of imatinib treated GIST mice (center panel, right half). Intracellular Ido expression in CD45+ intratumoral immune cells and CD45−Kit+ tumor cells as determined by flow cytometry (right panel). (b) Tumor weight of GIST mice treated with 1-MT for 7 d with or without CD8+ T cell depletion. (c–i) GIST mice were treated for 7 d with combinations of 1-MT or control (Ctrl), imatinib (I), or vehicle (V), and tryptophan metabolites (metabs). Tumors and DLNs were analyzed using flow cytometry. (c) Frequency of intratumoral CD8+Ki67+ and CD8+CD69+ T cells. (d) Frequency of intratumoral Annexin V+ T regs. (e) Intratumoral CD8+ T cell to T reg ratio. (f) Tumor weight. (g) MFI and frequency of intratumoral CD8+CD69+ and CD8+granzyme B+ T cells. (h) Frequency of intratumoral Annexin V+ T regs. (i) Intratumoral CD8+ T cell to T reg ratio. Data in (a) left panel represent means ± s.e.m. and are shown relative to internal controls (housekeeping gene). Data represent means ± s.e.m. with n = 6–12 per group. *P < 0.05.

Mentions: To identify how imatinib affected intratumoral CD8+ T cells and T regs, we performed gene expression array analysis of mouse GIST tumors. Among the largest differences after imatinib was a reduction in intratumoral Ido mRNA (Supplementary Table 1; Fig. 3a, left panel). Immunomodulatory cytokines IL-1β, IL-6, TNF-α, IL-17, IL-10, and IFN-γ were not altered by imatinib (Supplementary Fig. 5). Ido is a protein that catalyzes the conversion of tryptophan into immunosuppressive metabolites, which promote the development, stabilization, and activation of T regs while also suppressing effector T cells.16–21 Western blot confirmed that Ido protein was expressed at high levels at baseline within the tumor but not in the DLN or spleen, and was decreased substantially by imatinib (Fig. 3a, center). Ido protein was present in CD45− Kit+ tumor cells but not CD45+ intratumoral lymphocytes (Fig. 3a, right). The overall reduction in tumor Ido protein by imatinib did not result merely from the loss of tumor cells, since Ido protein was also decreased on a per cell basis in live tumor cells (Fig. 3a, right).


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)

Imatinib alters intratumoral T cells through inhibition of Ido(a) Ido mRNA in the DLN and tumor as determined by microarray analysis of vehicle treated GIST mice and the tumor from imatinib treated GIST mice after 7 days (left panel, n = 3 per group). Western blot (WB) staining for Ido in the DLN, spleen (center panel, left half), and tumor of vehicle treated GIST mice and tumor of imatinib treated GIST mice (center panel, right half). Intracellular Ido expression in CD45+ intratumoral immune cells and CD45−Kit+ tumor cells as determined by flow cytometry (right panel). (b) Tumor weight of GIST mice treated with 1-MT for 7 d with or without CD8+ T cell depletion. (c–i) GIST mice were treated for 7 d with combinations of 1-MT or control (Ctrl), imatinib (I), or vehicle (V), and tryptophan metabolites (metabs). Tumors and DLNs were analyzed using flow cytometry. (c) Frequency of intratumoral CD8+Ki67+ and CD8+CD69+ T cells. (d) Frequency of intratumoral Annexin V+ T regs. (e) Intratumoral CD8+ T cell to T reg ratio. (f) Tumor weight. (g) MFI and frequency of intratumoral CD8+CD69+ and CD8+granzyme B+ T cells. (h) Frequency of intratumoral Annexin V+ T regs. (i) Intratumoral CD8+ T cell to T reg ratio. Data in (a) left panel represent means ± s.e.m. and are shown relative to internal controls (housekeeping gene). Data represent means ± s.e.m. with n = 6–12 per group. *P < 0.05.
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Figure 3: Imatinib alters intratumoral T cells through inhibition of Ido(a) Ido mRNA in the DLN and tumor as determined by microarray analysis of vehicle treated GIST mice and the tumor from imatinib treated GIST mice after 7 days (left panel, n = 3 per group). Western blot (WB) staining for Ido in the DLN, spleen (center panel, left half), and tumor of vehicle treated GIST mice and tumor of imatinib treated GIST mice (center panel, right half). Intracellular Ido expression in CD45+ intratumoral immune cells and CD45−Kit+ tumor cells as determined by flow cytometry (right panel). (b) Tumor weight of GIST mice treated with 1-MT for 7 d with or without CD8+ T cell depletion. (c–i) GIST mice were treated for 7 d with combinations of 1-MT or control (Ctrl), imatinib (I), or vehicle (V), and tryptophan metabolites (metabs). Tumors and DLNs were analyzed using flow cytometry. (c) Frequency of intratumoral CD8+Ki67+ and CD8+CD69+ T cells. (d) Frequency of intratumoral Annexin V+ T regs. (e) Intratumoral CD8+ T cell to T reg ratio. (f) Tumor weight. (g) MFI and frequency of intratumoral CD8+CD69+ and CD8+granzyme B+ T cells. (h) Frequency of intratumoral Annexin V+ T regs. (i) Intratumoral CD8+ T cell to T reg ratio. Data in (a) left panel represent means ± s.e.m. and are shown relative to internal controls (housekeeping gene). Data represent means ± s.e.m. with n = 6–12 per group. *P < 0.05.
Mentions: To identify how imatinib affected intratumoral CD8+ T cells and T regs, we performed gene expression array analysis of mouse GIST tumors. Among the largest differences after imatinib was a reduction in intratumoral Ido mRNA (Supplementary Table 1; Fig. 3a, left panel). Immunomodulatory cytokines IL-1β, IL-6, TNF-α, IL-17, IL-10, and IFN-γ were not altered by imatinib (Supplementary Fig. 5). Ido is a protein that catalyzes the conversion of tryptophan into immunosuppressive metabolites, which promote the development, stabilization, and activation of T regs while also suppressing effector T cells.16–21 Western blot confirmed that Ido protein was expressed at high levels at baseline within the tumor but not in the DLN or spleen, and was decreased substantially by imatinib (Fig. 3a, center). Ido protein was present in CD45− Kit+ tumor cells but not CD45+ intratumoral lymphocytes (Fig. 3a, right). The overall reduction in tumor Ido protein by imatinib did not result merely from the loss of tumor cells, since Ido protein was also decreased on a per cell basis in live tumor cells (Fig. 3a, right).

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