Upregulation of HLA Class I Expression on Tumor Cells by the Anti-EGFR Antibody Nimotuzumab

Abstract

Defining how epidermal growth factor receptor (EGFR)-targeting therapies influence the immune response is essential to increase their clinical efficacy. A growing emphasis is being placed on immune regulator genes that govern tumor -T cell interactions. Previous studies showed an increase in HLA class I cell surface expression in tumor cell lines treated with anti-EGFR agents. In particular, earlier studies of the anti-EGFR blocking antibody cetuximab, have suggested that increased tumor expression of HLA class I is associated with positive clinical response. We investigated the effect of another commercially available anti-EGFR antibody nimotuzumab on HLA class I expression in tumor cell lines. We observed, for the first time, that nimotuzumab increases HLA class I expression and its effect is associated with a coordinated increase in mRNA levels of the principal antigen processing and presentation components. Moreover, using 7A7 (a specific surrogate antibody against murine EGFR), we obtained results suggesting the importance of the increased MHC-I expression induced by EGFR-targeted therapies display higher in antitumor immune response. 7A7 therapy induced upregulation of tumor MHC-I expression in vivo and tumors treated with this antibody display higher susceptibility to CD8 + T cells-mediated lysis. Our results represent the first evidence suggesting the importance of the adaptive immunity in nimotuzumabmediated antitumor activity. More experiments should be conducted in order to elucidate the relevance of this mechanism in cancer patients. This novel immune-related antitumor mechanism mediated by nimotuzumab opens new perspectives for its combination with various immunotherapeutic agents and cancer vaccines.

EGFR‐targeted therapy alters the tumor microenvironment in EGFR‐driven lung tumors: Implications for combination therapies

“…14,15 In addition, EGFR-TKIs can potentiate the induction of MHC class I and II molecules in response to IFN-γ and enhance T cell-mediated tumor killing. 16,17 These studies support the potential synergistic effects of combining PD-1/PD-L1 inhibitors and EGFR targeted therapy in NSCLC patients. Although many clinical trials have attempted to explore this combination in NSCLC cases, the results have shown that the clinical benefits are far below expectations.…”

“…Preclinical results have shown that EGFR activation can upregulate intrinsic PD‐L1 expression on tumor cells, which induces T‐cell apoptosis and contributes to the immune escape of EGFR ‐mutant NSCLC . In addition, EGFR‐TKIs can potentiate the induction of MHC class I and II molecules in response to IFN‐γ and enhance T cell‐mediated tumor killing . These studies support the potential synergistic effects of combining PD‐1/PD‐L1 inhibitors and EGFR targeted therapy in NSCLC patients.…”

Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade

“…As deactivation of IFNGR1 did not lead to the downregulation of the PD-L1 and MHC-I molecules on TC-1/dIfngr1 and TC-1/A9/dIfngr1 cells in vivo compared to TC-1 and TC-1/A9 cells, respectively, we hypothesized that besides IFN-γ, other cytokines induced PD-L1 and MHC-I expression. Several studies have indicated the involvement of different factors (IFN-α, IFN-β, IL-27, EGF, TNF-α, IL-6, GM-CSF, IL-1α, and CCL2 combined with lipocalin 2) in PD-L1 and MHC-I stimulation or stabilization [27,[29][30][31][32][33][34][35][36][37][38][39]. In this study, type I IFNs (IFN-α and IFN-β) were the main inducers of PD-L1 and MHC-I expression.…”

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

“…It has been previously reported that expression of MHCI and/or MHCII molecules can impact the antitumor immune response [103][104][105]. IFN-γ potentiates the induction of MHC class I (MHCI) and II (MHCII) molecules [102,106]. Watanabe et al found that EGFR-mutant cells have lower levels of human leukocyte antigen (HLA)-B expression than do EGFR-wildtype cells [107] in the presence of IFN-γ.…”