Selective inhibition of mTORC1 in tumor vessels increases antitumor immunity
Shan Wang, Ariel Raybuck, Eileen Shiuan, Sung Hoon Cho, Qingfei Wang, Dana M. Brantley-Sieders, Deanna Edwards, Margaret M. Allaman, James Nathan, Keith T. Wilson, David DeNardo, Siyuan Zhang, Rebecca Cook, Mark Boothby, Jin Chen
Shan Wang, Ariel Raybuck, Eileen Shiuan, Sung Hoon Cho, Qingfei Wang, Dana M. Brantley-Sieders, Deanna Edwards, Margaret M. Allaman, James Nathan, Keith T. Wilson, David DeNardo, Siyuan Zhang, Rebecca Cook, Mark Boothby, Jin Chen
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Research Article Immunology Oncology

Selective inhibition of mTORC1 in tumor vessels increases antitumor immunity

Abstract

A tumor blood vessel is a key regulator of tissue perfusion, immune cell trafficking, cancer metastasis, and therapeutic responsiveness. mTORC1 is a signaling node downstream of multiple angiogenic factors in the endothelium. However, mTORC1 inhibitors have limited efficacy in most solid tumors, in part due to inhibition of immune function at high doses used in oncology patients and compensatory PI3K signaling triggered by mTORC1 inhibition in tumor cells. Here we show that low-dose RAD001/everolimus, an mTORC1 inhibitor, selectively targets mTORC1 signaling in endothelial cells (ECs) without affecting tumor cells or immune cells, resulting in tumor vessel normalization and increased antitumor immunity. Notably, this phenotype was recapitulated upon targeted inducible gene ablation of the mTORC1 component Raptor in tumor ECs (RaptorECKO). Tumors grown in RaptorECKO mice displayed a robust increase in tumor-infiltrating lymphocytes due to GM-CSF–mediated activation of CD103+ dendritic cells and displayed decreased tumor growth and metastasis. GM-CSF neutralization restored tumor growth and metastasis, as did T cell depletion. Importantly, analyses of human tumor data sets support our animal studies. Collectively, these findings demonstrate that endothelial mTORC1 is an actionable target for tumor vessel normalization, which could be leveraged to enhance antitumor immune therapies.

Authors

Shan Wang, Ariel Raybuck, Eileen Shiuan, Sung Hoon Cho, Qingfei Wang, Dana M. Brantley-Sieders, Deanna Edwards, Margaret M. Allaman, James Nathan, Keith T. Wilson, David DeNardo, Siyuan Zhang, Rebecca Cook, Mark Boothby, Jin Chen

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Figure 2

Raptor/mTORC1 loss in tumor endothelium decreases tumor growth and metastasis.

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Raptor/mTORC1 loss in tumor endothelium decreases tumor growth and metas...
(A) Schematic diagram showing the experimental procedure of tamoxifen treatment and subcutaneous implantation of LLC tumor nodules. (B) Representative image of bioluminescence signal from LLC tumors on WT control and RaptorECKO mice. (C) Growth curves of LLC tumors on WT control and RaptorECKO mice. Tumors were measured by a caliper every other day from day 10 through 20 after tumor implantation. n = 12 to 15 mice per group. **P ≤ 0.01, 2-way ANOVA. (D) Representative images of the lungs harvested from WT and RaptorECKO mice after 20 days of LLC tumor implantation. Arrows indicate metastatic foci on the surface of lungs, which were quantified. (E) Disease-free survival of spontaneous MMTV-PyMT tumors against age (weeks). n = 22 to 28 mice per group. **P ≤ 0.01. Statistical analysis was performed using log-rank test. (F) Growth curves of spontaneous MMTV-PyMT tumors on WT control and RaptorECKO mice. **P ≤ 0.01, 2-way ANOVA. (G) Representative H&E staining of lungs harvested from WT and RaptorECKO/MMTV-PyMT mice. Arrows indicate metastatic foci within the lungs, which were quantified. Scale bar: 200 μm. Unless indicated, all data are presented as mean ± SD, and P values were determined by 2-tailed unpaired Student’s 2-tailed t test. **P ≤ 0.01.