Abstract
Mutations underlying disease in tuberous sclerosis complex (TSC) give rise to tumors with biallelic mutations in TSC1 or TSC2 and hyperactive mammalian target of rapamycin complex 1 (mTORC1). Benign tumors might exhibit de novo expression of immunogens, targetable by immunotherapy. As tumors may rely on ganglioside D3 (GD3) expression for mTORC1 activation and growth, we compared GD3 expression in tissues from patients with TSC and controls. GD3 was overexpressed in affected tissues from patients with TSC and also in aging Tsc2+/– mice. As GD3 overexpression was not accompanied by marked natural immune responses to the target molecule, we performed preclinical studies with GD3 chimeric antigen receptor (CAR) T cells. Polyfunctional CAR T cells were cytotoxic toward GD3-overexpressing targets. In mice challenged with Tsc2–/– tumor cells, CAR T cells substantially and durably reduced the tumor burden, correlating with increased T cell infiltration. We also treated aged Tsc2+/– heterozygous (>60 weeks) mice that carry spontaneous Tsc2–/– tumors with GD3 CAR or untransduced T cells and evaluated them at endpoint. Following CAR T cell treatment, the majority of mice were tumor free while all control animals carried tumors. The outcomes demonstrate a strong treatment effect and suggest that targeting GD3 can be successful in TSC.
Highlights
Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem genetic disorder
We propose that ganglioside D3 (GD3) overexpression develops in response to platelet-derived growth factor (PDGF) stimulation of TSC2–/– cells and provides a survival advantage to host cells
Since GD3 can be cross-presented by antigen-presenting cells (APCs) and induce iNKT cell responses in a melanoma mouse model [34], we examined NKT cell infiltration in the microenvironment of tuberous sclerosis complex (TSC) patient tissues
Summary
Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem genetic disorder. TSC and lymphangioleiomyomatosis (LAM) are caused by biallelic mutations of the TSC1 or TSC2 genes, coding for tumor suppressors hamartin and tuberin, respectively. Biallelic mutations in a single gene give rise to benign tumors in vital organs, associated with constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) [1]. Clinical manifestations of TSC vary from skin discolorations to progressive development of tumors in multiple organs, including lungs, as in TSC-associated and sporadic LAM [2]. Neurological symptoms include epilepsy and long-term memory impairment [3], TSC-associated neuropsychiatric disorders [4], and autism [5]. TSC further predisposes patients to more aggressive tumors, including renal cell carcinoma [7]. There is an unmet need for effective treatment modalities [8]
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