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Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti-PD-1 response in NSCLC. | LitMetric

AI Article Synopsis

  • The study examines why only about 20% of lung cancer patients respond to PD-1/PD-L1 targeted therapies, focusing on two different murine lung cancer cell lines, CMT167 (responsive) and Lewis Lung Carcinoma (LLC) (resistant).
  • RNA sequencing showed that CMT167 cells trigger an interferon-gamma (IFNγ) response not seen in LLC cells, indicating a key difference in their immune responses.
  • By manipulating IFNγ signaling, researchers found that LLC tumors could become more sensitive to treatment by enhancing immune cell activity and altering the tumor environment, leading to better responses to therapy.

Article Abstract

Targeting PD-1/PD-L1 is only effective in ∼20% of lung cancer patients, but determinants of this response are poorly defined. We previously observed differential responses of two murine K-Ras-mutant lung cancer cell lines to anti-PD-1 therapy: CMT167 tumors were eliminated, whereas Lewis Lung Carcinoma (LLC) tumors were resistant. The goal of this study was to define mechanism(s) mediating this difference. RNA sequencing analysis of cancer cells recovered from lung tumors revealed that CMT167 cells induced an IFNγ signature that was blunted in LLC cells. Silencing in CMT167 resulted in tumors resistant to IFNγ and anti-PD-1 therapy. Conversely, LLC cells had high basal expression of SOCS1, an inhibitor of IFNγ. Silencing increased response to IFNγ in vitro and sensitized tumors to anti-PD-1. This was associated with a reshaped tumor microenvironment, characterized by enhanced T cell infiltration and enrichment of PD-L1 myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFNγ signaling can induce a cascade of changes associated with increased therapeutic vulnerability.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537751PMC
http://dx.doi.org/10.26508/lsa.201900328DOI Listing

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