Immune-Modulation by Epidermal Growth Factor Receptor Inhibitors: Implication on Anti-Tumor Immunity in Lung Cancer

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.

Role of the dynamic tumor microenvironment in controversies regarding immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations

“…Additionally, several recent studies report that MHC-I and MHC-II expression is downregulated via the IFN-γ signaling pathway and downstream MEK/ERK signaling pathways (Fig. 2) [102,[107][108][109][110][111].…”

“…To date, preclinical and clinical studies have shown that EGFR-TKIs can induce antitumor immunity through the following [45,79,102,107,108,[153][154][155][156]: potentiating induction of class I (MHCI) and II (MHCII) molecules; promoting Foxp3 degradation to attenuate the inhibitory function of Tregs; reducing the infiltration of Tregs in the TME and inhibiting tumor growth; and enhancing the cytotoxicity of cytotoxic T lymphocytes (CTLs) that mediate antitumor immune response, reduce T cell apoptosis, and increase IFN-γ secretion to enhance the immune system response. Thus, EGFR-TKIs show promising efficacy for anti-PD-1/PD-L1 treatment.…”

MAPK pathway activity plays a key role in PD‐L1 expression of lung adenocarcinoma cells

“…Expression of MHC-I is critical for tumor cell antigen presentation and the anti-tumoral immune response [31]. Because both MAPK and IFNγ signaling can influence MHC-I expression, we wondered whether EGFR and MEK1/2 blockade could interfere with its expression in our cell lines [32][33][34]. IFNγ, but not EGF, increased MHC-I membrane expression in four of five cell lines ( Figure 4D and supplementary material, Figure S4C).…”

Basis of PD1/PD-L1 Therapies

“…Thus, PD-L1 expression can be induced by EGF signaling and enhanced by activating mutations in the EGF-R gene and contributes to the EGF-R-driven immune escape [85]. In addition, the Ras/Raf/MEK/MAPK-ERK pathway was also linked to PD-L1 overexpression in various cancers, while respective inhibitors lead to a downregulation of PD-L1 expression [86,87]. PD-L1 expression could be upregulated by cell contact.…”