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 8

Sequential treatment of rapamycin followed by PD-1 blockade slows tumor regrowth.

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Sequential treatment of rapamycin followed by PD-1 blockade slows tumor ...
(A) Schematic representation of treatment schedule. Mice carrying s.c. TSC2-deficient 105K tumors were treated with rapamycin (3 mg/kg) or vehicle every 2 days for 6 treatments in total. Twenty-four hours following the last rapamycin treatment, rapamycin-treated mice received isotype control or αPD-1 every 3 days for 4 treatments in total and were followed up to 36 days. (B) Tumor growth analysis of 105K tumor-bearing mice receiving vehicle (n = 8) or rapamycin treatment (n = 14). Data are presented as mean ± SD. Statistical significance was determined by Mann-Whitney U test, ****P < 0.0001. (C) Tumor growth analysis of 105K tumor–bearing mice pretreated with rapamycin and then receiving isotype control (n = 7) or αPD-1 antibody (n = 11). (D) The average tumor volume difference of the isotype control or αPD-1 antibody–treated group after the last antibody treatment (day 22) and the final measurement (day 36) is shown. Data are presented as mean ± SD. Statistical significance was determined by Mann-Whitney U test. (E) Tumor-free survival analysis of mice bearing TSC2-deficient 105K tumors treated as indicated (n = 7–11 per group). Statistical significance was determined by Log-rank test. ***P < 0.001; ****P < 0.0001.