Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis
Open Access
- 24 January 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (7), 1813-1826
- https://doi.org/10.1158/0008-5472.CAN-20-2808
Abstract
Small cell lung cancer (SCLC) is a pulmonary neuroendocrinc cancer with very poor prognosis and limited effective therapeutic options. Most patients are diagnosed at advanced stages, and the exact reason for the aggressive and metastatic phenotype of SCLC is completely unknown. Despite a high tumor mutational burden, responses to immune checkpoint blockade are minimal in patients with SCLC. This may reflect defects in immune surveillance. Here we illustrate that evading natural killer (NK) surveillance contributes to SCLC aggressiveness and metastasis, primarily through loss of NK-cell recognition of these tumors by reduction of NK-activating ligands (NKG2DL). SCLC primary tumors expressed very low level of NKG2D1, mRNA and SCLC lines express little to no surface NKG2D1, at the protein level. Chromatin immunoprecipitation sequencing showed NKG2DL loci in SCLC are inaccessible compared with NSCLC, with few H3K27Ac signals. Restoring NKG2DL in preclinical models suppressed tumor growth and metastasis in an NK cell-dependent manner. Likewise, histone deacetylase inhibitor treatment induced NKG2DI, expression and led to tumor suppression by inducing infiltration and activation of NK and T cells. Among all the common tumor types, SCLC and neuroblastoma were the lowest NKG2DL-expressing tumors, highlighting a lineage dependency of this phenotype. In conclusion, these data show that epigenetic silencing of NKG2DL results in a lack of stimulatory signals to engage and activate NK cells, highlighting the underlying immune avoidance of SCLC and neuroblastoma. Significance: This study discovers in SCLC and neuroblastoma impairment of an inherent mechanism of recognition of tumor cells by innate immunity and proposes that this mechanism can be reactivated to promote immune surveillance.Other Versions
Funding Information
- Cancer Prevention and Research Institute of Texas
- Scholar Award (RR160080)
- NIH (CA070907)
- Welch Foundation (1975-20190330, CA070907, CA213338, CA213274)
- J.E. Johnson (CA213338)
This publication has 46 references indexed in Scilit:
- The Narrow-Spectrum HDAC Inhibitor Entinostat Enhances NKG2D Expression Without NK Cell Toxicity, Leading to Enhanced Recognition of Cancer CellsPharmaceutical Research, 2013
- Regulation of Ligands for the NKG2D Activating ReceptorAnnual Review of Immunology, 2013
- The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivityNature, 2012
- Histone deacetylase inhibitors impair NK cell viability and effector functions through inhibition of activation and receptor expressionJournal of Leukocyte Biology, 2011
- Natural Killer Cells: From Basic Research to TreatmentsFrontiers in Immunology, 2011
- MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myelomaProceedings of the National Academy of Sciences of the United States of America, 2008
- Proteolytic Release of Soluble UL16-Binding Protein 2 from Tumor CellsCancer Research, 2006
- Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cellsBlood, 2004
- Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activationNature, 2002
- Markedly decreased expression of class I histocompatibility antigens, protein, and mRNA in human small-cell lung cancer.The Journal of Experimental Medicine, 1985