Abstract
Skin toxicity is the most common toxicity caused by Epidermal Growth Factor Receptor (EGFR) inhibitors, and has been associated with clinical efficacy. As EGFR inhibitors enhance the expression of antigen presenting molecules in affected skin keratinocytes, they may concurrently facilitate neo-antigen presentation in lung cancer tumor cells contributing to anti-tumor immunity. Here, we investigated the modulatory effect of the EGFR inhibitor, erlotinib on antigen presenting molecules and PD-L1, prominent immune checkpoint protein, of skin keratinocytes and lung cancer cell lines to delineate the link between EGFR signaling pathway inhibition and potential anti-tumor immunity. Erlotinib up-regulated MHC-I and MHC-II proteins on IFNγ treated keratinocytes but abrogated IFNγ-induced expression of PD-L1, suggesting the potential role of infiltrating autoreactive T cells in the damage of keratinocytes in affected skin. Interestingly, the surface expression of MHC-I, MHC-II, and PD-L1 was up-regulated in response to IFNγ more often in lung cancer cell lines sensitive to erlotinib, but only expression of PD-L1 was inhibited by erlotinib. Further, erlotinib significantly increased T cell mediated cytotoxicity on lung cancer cells. Lastly, the analysis of gene expression dataset of 186 lung cancer cell lines from Cancer Cell Line Encyclopedia demonstrated that overexpression of PD-L1 was associated with sensitivity to erlotinib and higher expression of genes related to antigen presenting pathways and IFNγ signaling pathway. Our findings suggest that the EGFR inhibitors can facilitate anti-tumor adaptive immune responses by breaking tolerance especially in EGFR driven lung cancer that are associated with overexpression of PD-L1 and genes related to antigen presentation and inflammation.
Highlights
Lung cancer remains a leading cause of cancer death in the Unites States, with 158,040 estimated death to occur in 2015 [1]
We decided to use another skin keratinocyte cell line, HaCaT cells for our analysis because they are known to express a comparable level of Epidermal Growth Factor Receptor (EGFR) to primary skin keratinocyte so that we could extrapolate the modulatory effect of EGFR inhibitors observed in HaCaT cells to what might happen in primary skin keratinocytes in physiologic condition [37]
As we showed that lung cancer cell lines sensitive to EGFR inhibitors expressed a trend towards higher baseline levels of MHC-I and PD-L1, and higher expression of PD-L1, MHC-I, and MHC-II in response to IFNγ, we investigated whether PD-L1 overexpression is associated with overexpression of other immune-related genes in 186 lung cancer cell lines from cell line encyclopedia (CCLE) database
Summary
Lung cancer remains a leading cause of cancer death in the Unites States, with 158,040 estimated death to occur in 2015 [1]. 16.8% of patients with lung cancer of all stages survive more than 5 year, and 5 year survival rate for advanced stage or metastatic lung cancer patients are dismal [2]. Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) are frontline therapy for advanced or metastatic non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations such as exon 19 deletion or exon 21 L858R mutation [3]. About 10% of Caucasian and up to 50% of Asian patients with NSCLC harbor sensitizing mutations and respond to EGFR inhibitors resulting in a dramatic disease control with the improvement of symptoms. One of resistant mechanisms is the acquisition of the resistant mutation, T790M, and it has been reported to occur in 50% of patients after the disease progression on EGFR inhibitors [5,6]
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