TSC2-deficient tumors have evidence of T cell exhaustion and respond to anti–PD-1/anti–CTLA-4 immunotherapy
Heng-Jia Liu, … , Arlene H. Sharpe, Elizabeth P. Henske
Heng-Jia Liu, … , Arlene H. Sharpe, Elizabeth P. Henske
Published April 19, 2018
Citation Information: JCI Insight. 2018;3(8):e98674. https://doi.org/10.1172/jci.insight.98674.
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Research Article Oncology

TSC2-deficient tumors have evidence of T cell exhaustion and respond to anti–PD-1/anti–CTLA-4 immunotherapy

Abstract

Tuberous sclerosis complex (TSC) is an incurable multisystem disease characterized by mTORC1-hyperactive tumors. TSC1/2 mutations also occur in other neoplastic disorders, including lymphangioleiomyomatosis (LAM) and bladder cancer. Whether TSC-associated tumors will respond to immunotherapy is unknown. We report here that the programmed death 1 coinhibitory receptor (PD-1) is upregulated on T cells in renal angiomyolipomas (AML) and pulmonary lymphangioleiomyomatosis (LAM). In C57BL/6J mice injected with syngeneic TSC2-deficient cells, anti–PD-1 alone decreased 105K tumor growth by 67% (P < 0.0001); the combination of PD-1 and CTLA-4 blockade was even more effective in suppressing tumor growth. Anti–PD-1 induced complete rejection of TSC2-deficient 105K tumors in 37% of mice (P < 0.05). Double blockade of PD-1 and CTLA-4 induced rejection in 62% of mice (P < 0.01). TSC2 reexpression in TSC2-deficient TMKOC cells enhanced antitumor immunity by increasing T cell infiltration and production of IFN-γ/TNF-α by T cells, suggesting that TSC2 and mTORC1 play specific roles in the induction of antitumor immunity. Finally, 1 month of anti–PD-1 blockade reduced renal tumor burden by 53% (P < 0.01) in genetically engineered Tsc2+/– mice. Taken together, these data demonstrate for the first time to our knowledge that checkpoint blockade may have clinical efficacy for TSC and LAM, and possibly other benign tumor syndromes, potentially yielding complete and durable clinical responses.

Authors

Heng-Jia Liu, Patrick H. Lizotte, Heng Du, Maria C. Speranza, Hilaire C. Lam, Spencer Vaughan, Nicola Alesi, Kwok-Kin Wong, Gordon J. Freeman, Arlene H. Sharpe, Elizabeth P. Henske

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Figure 9

Reexpression of TSC2 in TSC2-deficient tumors enhances T cell–mediated antitumor immunity and promotes dual PD-1 and CTLA-4 blockade.

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Reexpression of TSC2 in TSC2-deficient tumors enhances T cell–mediated a...
(A) Whole cell lysates from TSC2-null TMKOC cells and TSC2 add-back TMKOC cells were analyzed by immunoblotting with antibodies against TSC2 and β-actin. (B) Tumor growth curve of mice bearing TSC2-null TMKOC tumors or TSC2 add-back TMKOC tumors (n = 6 per group). Data are presented as mean ± SD. Statistical significance was determined by Mann-Whitney U test. (C) Tumor-free survival analysis of mice bearing TSC2-null TMKOC or TSC2 add-back TMKOC tumors. (D–F) Tumors from mice injected with TSC2-null TMKOC or TSC2 add-back TMKOC cells were harvested and analyzed for CD45+ hematopoietic lineage cells with lymphocytes and myeloid markers by flow cytometry: (D) CD45+ cells and CD11b+ myeloid cells, (E) CD8+ and CD4+ T cells, and (F) CD8+ and CD4+ T cell intracellular IFN-γ and TNF-α production. (G) Ki-67 expression in CD8+ and CD4+ T cells. Data are presented as mean ± SD. Statistical significance was determined by Mann-Whitney U test. (H) Tumor growth curve of mice bearing TSC2-null TMKOC tumors or TSC2 add-back TMKOC tumors treated with isotype control or combined anti–PD-1 and anti–CTLA-4 antibodies (n = 10 per group). Data are presented as mean ± SD. Statistical significance was determined by nonparametric 1-way ANOVA followed by Dunn’s multiple comparison test. (I) Overall survival analysis of mice bearing TSC2-null TMKOC or TSC2 add-back TMKOC tumors treated as described in H (n = 14 per group). Statistical significance was determined by Log-rank test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. (J) Percentage of mice bearing s.c. TSC2-null or TSC2 add-back TMKOC tumors treated as described in H that completely rejected their tumors.