Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

Oncoimmunology
Sophie LangdonCharles Sinclair

Abstract

mTOR inhibition can promote or inhibit immune responses in a context dependent manner, but whether this will represent a net benefit or be contraindicated in the context of immunooncology therapies is less understood. Here, we report that the mTORC1/2 dual kinase inhibitor vistusertib (AZD2014) potentiates anti-tumour immunity in combination with anti-CTLA-4 (αCTLA-4), αPD-1 or αPD-L1 immune checkpoint blockade. Combination of vistusertib and immune checkpoint blocking antibodies led to tumour growth inhibition and improved survival of MC-38 or CT-26 pre-clinical syngeneic tumour models, whereas monotherapies were less effective. Underlying these combinatorial effects, vistusertib/immune checkpoint combinations reduced the occurrence of exhausted phenotype tumour infiltrating lymphocytes (TILs), whilst increasing frequencies of activated Th1 polarized T-cells in tumours. Vistusertib alone was shown to promote a Th1 polarizing proinflammatory cytokine profile by innate primary immune cells. Moreover, vistusertib directly enhanced activation of effector T-cell and survival, an effect that was critically dependent on inhibitor dose. Therefore, these data highlight direct, tumour-relevant immune potentiating benefits of mTOR inhibi...Continue Reading

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Jul 6, 2020·International Immunology·Alok Kumar, Kenji Chamoto
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Methods Mentioned

BETA
flow cytometry
ELISA
FCS
PCR

Clinical Trials Mentioned

NCT02423954
NCT02890069

Software Mentioned

Graphpad Prism
viSNE
Jmp®13
FlowJo
Cytobank
GraphPrism®
fluidigm
Spotfire®
Meso Scale Discovery
Fluidigm Real - Time PCR Analysis

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