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

Research output: Contribution to journalArticle

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

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.

Original languageEnglish (US)
JournalJCI insight
Volume3
Issue number13
DOIs
StatePublished - Jul 12 2018

PMID: 29997286

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Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival. / Markowitz, Geoffrey J.; Havel, Lauren S.; Crowley, Michael Jp; Ban, Yi; Lee, Sharrell B.; Thalappillil, Jennifer S.; Narula, Navneet; Bhinder, Bhavneet; Elemento, Olivier; Wong, Stephen T.; Gao, Dingcheng; Altorki, Nasser K.; Mittal, Vivek.

In: JCI insight, Vol. 3, No. 13, 12.07.2018.

Research output: Contribution to journalArticle

Harvard

Markowitz, GJ, Havel, LS, Crowley, MJ, Ban, Y, Lee, SB, Thalappillil, JS, Narula, N, Bhinder, B, Elemento, O, Wong, ST, Gao, D, Altorki, NK & Mittal, V 2018, 'Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival' JCI insight, vol. 3, no. 13. https://doi.org/10.1172/jci.insight.96836

APA

Markowitz, G. J., Havel, L. S., Crowley, M. J., Ban, Y., Lee, S. B., Thalappillil, J. S., ... Mittal, V. (2018). Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival. JCI insight, 3(13). https://doi.org/10.1172/jci.insight.96836

Vancouver

Markowitz GJ, Havel LS, Crowley MJ, Ban Y, Lee SB, Thalappillil JS et al. Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival. JCI insight. 2018 Jul 12;3(13). https://doi.org/10.1172/jci.insight.96836

Author

Markowitz, Geoffrey J. ; Havel, Lauren S. ; Crowley, Michael Jp ; Ban, Yi ; Lee, Sharrell B. ; Thalappillil, Jennifer S. ; Narula, Navneet ; Bhinder, Bhavneet ; Elemento, Olivier ; Wong, Stephen T. ; Gao, Dingcheng ; Altorki, Nasser K. ; Mittal, Vivek. / Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival. In: JCI insight. 2018 ; Vol. 3, No. 13.

BibTeX

@article{4e746dee0833415fab55b4f31a49a48f,
title = "Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival",
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.",
keywords = "Cancer immunotherapy, Immunology, Lung cancer, Oncology, T cells",
author = "Markowitz, {Geoffrey J.} and Havel, {Lauren S.} and Crowley, {Michael Jp} and Yi Ban and Lee, {Sharrell B.} and Thalappillil, {Jennifer S.} and Navneet Narula and Bhavneet Bhinder and Olivier Elemento and Wong, {Stephen T.} and Dingcheng Gao and Altorki, {Nasser K.} and Vivek Mittal",
year = "2018",
month = "7",
day = "12",
doi = "10.1172/jci.insight.96836",
language = "English (US)",
volume = "3",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "13",

}

RIS

TY - JOUR

T1 - Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival

AU - Markowitz, Geoffrey J.

AU - Havel, Lauren S.

AU - Crowley, Michael Jp

AU - Ban, Yi

AU - Lee, Sharrell B.

AU - Thalappillil, Jennifer S.

AU - Narula, Navneet

AU - Bhinder, Bhavneet

AU - Elemento, Olivier

AU - Wong, Stephen T.

AU - Gao, Dingcheng

AU - Altorki, Nasser K.

AU - Mittal, Vivek

PY - 2018/7/12

Y1 - 2018/7/12

N2 - 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.

AB - 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.

KW - Cancer immunotherapy

KW - Immunology

KW - Lung cancer

KW - Oncology

KW - T cells

UR - http://www.scopus.com/inward/record.url?scp=85057417973&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057417973&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.96836

DO - 10.1172/jci.insight.96836

M3 - Article

VL - 3

JO - JCI Insight

T2 - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 13

ER -

ID: 47279461