Abstract A94: Imatinib modulates CD4+ T cells in gastrointestinal stromal tumor (GIST). Free

Introduction: Imatinib mesylate partially exerts its antitumor effects in GIST by inhibiting tumor production of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido), thereby activating antitumor CD8⁺ T cells. The role of conventional CD4⁺ T cells (CD4⁺FoxP3^-) in imatinib therapy is unknown. We examined the effects of imatinib on CD4⁺ T cells in GIST.

Methods: We injected imatinib or saline intraperitoneally for one week to KitV558^-/+ mice that develop spontaneous GISTs. 1-methyl-D-tryptophan (D-1MT), an Ido inhibitor was given via oral gavage. We assessed treatment response by tumor weight and immune cells by flow cytometry. Regulatory T cells (Treg) were defined as CD4⁺FoxP3⁺. Matched blood and tumor specimens from GIST patients were freshly analyzed for immune composition. Tumors were classified as untreated, sensitive, or resistant to imatinib based on radiologic assessment just before the time of surgery.

Results: Imatinib increased CD4⁺ number, activation, and degranulation in the draining lymph node (DLN) but not the spleen of GIST mice (p<0.05). In the tumor, imatinib increased CD4⁺ number, activation, proliferation, and the intratumoral CD4⁺/Treg ratio (p<0.05). Conversely, Ido inhibition did not alter CD4⁺ number, activation, proliferation, or the CD4⁺/Treg ratio in the DLN or tumor. In untreated human GISTs (n=14), CD4⁺ T cells demonstrated greater activation and memory phenotype compared to autologous blood CD4⁺ T cells, but secreted T_h2 cytokines on in vitro restimulation (p<0.05). Imatinib treatment altered the intratumoral CD4⁺/Treg ratio, with a higher ratio in sensitive tumors (n=17) compared to resistant tumors (n=12; p<0.05).

Conclusion: In mouse GIST, imatinib activates CD4⁺ T cells independently of Ido and increases the intratumoral CD4⁺/Treg ratio, a hallmark of immunologic outcome. Similarly, imatinib sensitive human GISTs have a higher CD4⁺/Treg ratio than resistant tumors. Hence, CD4⁺ T cells may contribute to the antitumor effects of imatinib in GIST. Combination immunotherapy with imatinib and CD4⁺ T cell modulating agents may be a promising therapy for GIST.

Citation Format: Vinod P. Balachandran, Michael Cavnar, Shan Zeng, Zubin Bamboat, Lee Ocuin, Hebroon Obaid, Eric Sorenson, Teresa Kim, Rachel Popow, Ronald P. DeMatteo. Imatinib modulates CD4+ T cells in gastrointestinal stromal tumor (GIST). [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A94.