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Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis
Mingrui Zhu1,2, Yi Huang1,2, Matthew E Bender1,2
1Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.
Abstract:
Small cell lung cancer (SCLC) is a pulmonary neuroendocrine 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 NKG2DL mRNA and SCLC lines express little to no surface NKG2DL 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 NKG2DL 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.
Insights
Small cell lung cancer (SCLC) evades natural killer (NK) cell surveillance by epigenetically silencing NK-activating ligands (NKG2DL). Reactivating NKG2DL expression suppresses SCLC growth and metastasis, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Small cell lung cancer (SCLC) has a poor prognosis and limited treatment options, often diagnosed at advanced stages.
- The aggressive and metastatic nature of SCLC is not fully understood, and responses to immune checkpoint inhibitors are minimal.
- Defects in immune surveillance, particularly by natural killer (NK) cells, may contribute to SCLC's aggressiveness.
Purpose of the Study:
- To investigate the role of NK cell surveillance evasion in SCLC aggressiveness and metastasis.
- To identify the mechanisms by which SCLC evades NK cell recognition.
- To explore therapeutic strategies targeting NK cell recognition in SCLC.
Main Methods:
- Analysis of NK-activating ligand (NKG2DL) expression in SCLC tumors and cell lines at mRNA and protein levels.
- Chromatin immunoprecipitation sequencing to assess NKG2DL accessibility in SCLC.
- Preclinical models to evaluate the effect of restoring NKG2DL expression and histone deacetylase inhibitor treatment on tumor growth and metastasis.
- Assessment of NK and T cell infiltration and activation.
Main Results:
- SCLC tumors and cell lines exhibit significantly reduced expression of NKG2DL.
- NKG2DL loci in SCLC are epigenetically silenced, indicated by inaccessible chromatin and low H3K27Ac signals.
- Restoring NKG2DL expression in preclinical models suppressed SCLC tumor growth and metastasis in an NK cell-dependent manner.
- Histone deacetylase inhibitor treatment increased NKG2DL expression, suppressed tumors, and enhanced NK and T cell activity.
- SCLC and neuroblastoma show the lowest NKG2DL expression among common tumor types, suggesting a lineage-dependent phenotype.
Conclusions:
- Epigenetic silencing of NKG2DL contributes to immune evasion in SCLC and neuroblastoma by preventing NK cell activation.
- Restoring NKG2DL expression represents a potential therapeutic approach to enhance immune surveillance against SCLC.
- This study highlights the impairment of innate immune recognition in SCLC and neuroblastoma and proposes reactivation as a strategy for immune surveillance.
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