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Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival
Geoffrey J. Markowitz, … , Nasser K. Altorki, Vivek Mittal
Geoffrey J. Markowitz, … , Nasser K. Altorki, Vivek Mittal
Published July 12, 2018
Citation Information: JCI Insight. 2018;3(13):e96836. https://doi.org/10.1172/jci.insight.96836.
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Research Article Immunology Oncology

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

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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 targeting of this axis early in lung cancer progression.

Authors

Geoffrey J. Markowitz, Lauren S. Havel, Michael J.P. Crowley, Yi Ban, Sharrell B. Lee, Jennifer S. Thalappillil, Navneet Narula, Bhavneet Bhinder, Olivier Elemento, Stephen T.C. Wong, Dingcheng Gao, Nasser K. Altorki, Vivek Mittal

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Figure 1

Prevalent PD-1/PD-L1 axis in early-stage human lung cancer patients.

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Prevalent PD-1/PD-L1 axis in early-stage human lung cancer patients.
(A)...
(A) Representative anti-CD3 IHC and H&E staining of tumor and matched adjacent nontumor tissue containing regions of samples from 3 representative early-stage lung cancer patients. (B) Flow cytometric analysis of lymphocytes from tumor (blue dots) and adjacent (red dots) tissue from early-stage human lung cancer patients. n = 9 per group. (C) Mean fluorescence intensity of PD-1 in CD4+ and CD8+ T cells in tumor (blue dots) and adjacent (red dots) tissue. n = 9 per group. (D) Representative immunofluorescence staining of tumor and adjacent tissue from early-stage lung cancer patients for CD45 (green), PD-L1 (red), EpCAM (white), and DAPI (blue). Tumor regions are labeled with T; adjacent tissue is labeled with A. Staining was performed on 8 samples. Scale bar: 20 μm. Magnifications for histological and immunohistochemical stains and scale bars for immunofluorescence stains are shown on the images themselves. Two-tailed unpaired t tests with Holm-Sidak correction for multiple comparisons; *P < 0.05, **P < 0.01.

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