TY - JOUR
T1 - Immune surveillance in clinical regression of preinvasive squamous cell lung cancer
AU - Pennycuick, Adam
AU - Teixeira, Vitor H.
AU - Abduljabbar, Khalid
AU - Ahmed Raza, Shan E.
AU - Lund, Tom
AU - Akarca, Ayse U.
AU - Rosenthal, Rachel
AU - Kalinke, Lukas
AU - Chandrasekharan, Deepak P.
AU - Pipinikas, Christodoulos P.
AU - Lee-Six, Henry
AU - Hynds, Robert E.
AU - Gowers, Kate H.C.
AU - Henry, Jake Y.
AU - Millar, Fraser R.
AU - Hagos, Yeman B.
AU - Denais, Celine
AU - Falzon, Mary
AU - Moore, David A.
AU - Antoniou, Sophia
AU - Durrenberger, Pascal F.
AU - Furness, Andrew J.
AU - Carroll, Bernadette
AU - Marceaux, Claire
AU - Asselin-Labat, Marie Liesse
AU - Larson, William
AU - Betts, Courtney
AU - Coussens, Lisa M.
AU - Thakrar, Ricky M.
AU - George, Jeremy
AU - Swanton, Charles
AU - Thirlwell, Christina
AU - Campbell, Peter J.
AU - Marafioti, Teresa
AU - Yuan, Yinyin
AU - Quezada, Sergio A.
AU - McGranahan, Nicholas
AU - Janes, Sam M.
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/10
Y1 - 2020/10
N2 - Before squamous cell lung cancer develops, precancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. Although recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of precancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in situ lesions harbor more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, CCL27–CCR10 signaling is upregulated, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the carcinoma in situ lesions, as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. SIGnIFICAnCE: Immune evasion is a hallmark of cancer. For the first time, this study identifies mechanisms by which precancerous lesions evade immune detection during the earliest stages of carcino-genesis and forms a basis for new therapeutic strategies that treat or prevent early-stage lung cancer.
AB - Before squamous cell lung cancer develops, precancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. Although recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of precancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in situ lesions harbor more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, CCL27–CCR10 signaling is upregulated, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the carcinoma in situ lesions, as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. SIGnIFICAnCE: Immune evasion is a hallmark of cancer. For the first time, this study identifies mechanisms by which precancerous lesions evade immune detection during the earliest stages of carcino-genesis and forms a basis for new therapeutic strategies that treat or prevent early-stage lung cancer.
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U2 - 10.1158/2159-8290.CD-19-1366
DO - 10.1158/2159-8290.CD-19-1366
M3 - Article
C2 - 32690541
AN - SCOPUS:85097172451
SN - 2159-8274
VL - 10
SP - 1489
EP - 1499
JO - Cancer discovery
JF - Cancer discovery
IS - 10
ER -