Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival

JCI Insight
Geoffrey J MarkowitzVivek Mittal

Abstract

Success of immune checkpoint inhibitors in advanced non-small-cell lung cancer (NSCLC) has invigorated their use in the neoadjuvant setting for early-stage disease. However, the cellular and molecular mechanisms of the early immune responses to therapy remain poorly understood. Through an integrated analysis of early-stage NSCLC patients and a Kras mutant mouse model, we show a prevalent programmed cell death 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis exemplified by increased intratumoral PD-1+ T cells and PD-L1 expression. Notably, tumor progression was associated with spatiotemporal modulation of the immune microenvironment with dominant immunosuppressive phenotypes at later phases of tumor growth. Importantly, PD-1 inhibition controlled tumor growth, improved overall survival, and reprogrammed tumor-associated lymphoid and myeloid cells. Depletion of T lymphocyte subsets demonstrated synergistic effects of those populations on PD-1 inhibition of tumor growth. Transcriptome analyses revealed T cell subset-specific alterations corresponding to degree of response to the treatment. These results provide insights into temporal evolution of the phenotypic effects of PD-1/PD-L1 activation and inhibition and motivate targe...Continue Reading

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Dec 12, 2018·Nature Reviews. Cancer·Nasser K AltorkiVivek Mittal
Mar 3, 2020·Frontiers in Immunology·Sara SaabHumam Kadara
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May 11, 2021·Frontiers in Oncology·Kayla F GoliwasJessy S Deshane
Jul 25, 2021·Cancers·Pasquale SaggeseClaudio Scafoglio

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Datasets Mentioned

BETA
GSE114300
GSE30431
PRJNA470948

Methods Mentioned

BETA
flow cytometry
exome sequencing
surgical resection

Clinical Trials Mentioned

NCT03197467

Software Mentioned

GraphPad Prism

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