Dataset Information

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-?/TNF-? 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.

SUBMITTER: Liu HJ

PROVIDER: S-EPMC5931128 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Liu Heng-Jia HJ Lizotte Patrick H PH Du Heng H Speranza Maria C MC Lam Hilaire C HC Vaughan Spencer S Alesi Nicola N Wong Kwok-Kin KK Freeman Gordon J GJ Sharpe Arlene H AH Henske Elizabeth P EP

JCI insight 20180419 8

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 inj ...[more]

PMID: 29669930

Similar Datasets

Project description:BackgroundHepatocellular carcinoma (HCC) is the most common form of primary liver cancer and is the third-leading cause of cancer-related death worldwide. Most patients with HCC are diagnosed at an advanced stage, and the median survival for patients with advanced HCC treated with modern systemic therapy is less than 2 years. This leaves the advanced stage patients with limited treatment options. Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) or its ligand, are widely used in the treatment of HCC and are associated with durable responses in a subset of patients. ICIs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) also have clinical activity in HCC. Combination therapy of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) is the first treatment option for HCC to be approved by Food and Drug Administration that targets more than one immune checkpoints.MethodsIn this study, we used the framework of quantitative systems pharmacology (QSP) to perform a virtual clinical trial for nivolumab and ipilimumab in HCC patients. Our model incorporates detailed biological mechanisms of interactions of immune cells and cancer cells leading to antitumor response. To conduct virtual clinical trial, we generate virtual patient from a cohort of 5,000 proposed patients by extending recent algorithms from literature. The model was calibrated using the data of the clinical trial CheckMate 040 (ClinicalTrials.gov number, NCT01658878).ResultsRetrospective analyses were performed for different immune checkpoint therapies as performed in CheckMate 040. Using machine learning approach, we predict the importance of potential biomarkers for immune blockade therapies.ConclusionsThis is the first QSP model for HCC with ICIs and the predictions are consistent with clinically observed outcomes. This study demonstrates that using a mechanistic understanding of the underlying pathophysiology, QSP models can facilitate patient selection and design clinical trials with improved success.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets