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

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

Research output: Contribution to journalArticle

17 Scopus citations

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.

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

Keywords

  • Cancer immunotherapy
  • Immunology
  • Lung cancer
  • Oncology
  • T cells

ASJC Scopus subject areas

  • Medicine(all)

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