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

TitleImmune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival.
Publication TypeJournal Article
Year of Publication2018
AuthorsMarkowitz GJ, Havel LS, Crowley MJp, Ban Y, Lee SB, Thalappillil JS, Narula N, Bhinder B, Elemento O, Wong STc, Gao D, Altorki NK, Mittal V
JournalJCI Insight
Date Published2018 07 12
KeywordsAnimals, Antibodies, Monoclonal, B7-H1 Antigen, Carcinoma, Non-Small-Cell Lung, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Disease Models, Animal, Disease Progression, Female, Humans, Immunotherapy, Lung, Lung Neoplasms, Mice, Mice, Inbred C57BL, Programmed Cell Death 1 Receptor, Proto-Oncogene Proteins p21(ras), T-Lymphocytes, Tumor Microenvironment

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.

Alternate JournalJCI Insight
PubMed ID29997286
PubMed Central IDPMC6101707
Grant ListT32 CA203702 / CA / NCI NIH HHS / United States
T32 GM008539 / GM / NIGMS NIH HHS / United States
U01 CA188388 / CA / NCI NIH HHS / United States