Tyrosine Kinase Inhibitors Stimulate HLA Class I Expression by Augmenting the IFNγ/STAT1 Signaling in Hepatocellular Carcinoma Cells

Abstract

Combination treatment with tyrosine kinase inhibitors (TKIs) and immunotherapies has shown efficacy in the treatment of multiple cancers, but the immunomodulatory effect of TKIs on the tumor cell phenotype remains unknown in hepatocellular carcinoma (HCC). Given that human lymphocyte antigen class I (HLA-I) is essential for tumor antigen presentation and subsequent antitumor immunity, we examined the effects of regorafenib, as well as other TKIs (sorafenib, lenvatinib and cabozantinib) on HLA-I expression in HCC cell lines. Regorafenib increased cell surface HLA-I and β2-microglobulin protein expression in the presence of interferon γ (IFNγ). The expressions of various genes associated with the HLA-I antigen processing pathway and its transcriptional regulators were also upregulated by regorafenib. Furthermore, we found that regorafenib had an activating effect on signal transducers and activators of transcription 1 (STAT1), and that regorafenib-induced HLA-I expression was dependent on the augmented IFNγ/STAT1 signaling pathway. Trametinib, an inhibitor of the extracellular signal-regulated kinase (ERK) kinase MEK, also activated IFNγ/STAT1 signaling and increased HLA-I expression, whereas the phosphatidylinositol 3-kinase (PI3K) inhibitor buparlisib did not. Given that regorafenib directly inhibits Raf/MEK/ERK signaling, the downregulation of the MEK/ERK pathway appears to be one of the mechanisms by which regorafenib promotes STAT1 activation. Sorafenib, lenvatinib, and cabozantinib also showed the same effects as regorafenib, while regorafenib had most potent effects on HLA-I expression, possibly dependent on its stronger inhibitory activity against the MEK/ERK pathway. These results support the clinical combination of TKIs with immunotherapy for the treatment of HCC.

Integration of miRNA:mRNA Co-Expression Revealed Crucial Mechanisms Modulated in Immunogenic Cancer Cell Death

“…Highly and differentially expressed mRNAs identified in this study suggested a new immunomodulatory activity of ICD inducers resulting in the regulation of antigen presentation, a crucial step for proper activation of the immune system antitumor response. Indeed, enrichment analysis demonstrated that the MHC-I pathway was upregulated, as previously reported [ 45 , 46 ], whereas MHC-II was downregulated. An in silico analysis of publicly available database [ 16 ] showed high concordance with our results, generalizing our findings, especially those regarding the downregulation of class II MHC molecules, an event associated to ICD induction altogether rather than to the specific ICD-inducing anticancer treatment.…”

Multikinase inhibitors modulate non-constitutive proteasome expression in colorectal cancer cells

“…Importantly, MKIs were shown to induce immunomodulatory effects. For instance, previous studies demonstrated that exposure to MKIs including sorafenib and regorafenib can stimulate MHCI synthesis and expression of other components of the antigen presentation pathway in cancer cells and, consequently, stimulate their elimination by cytotoxic lymphocytes ( Kwilas et al, 2014 ; Tsai et al, 2017 ; Takahashi et al, 2021 ). At the same time, little is known regarding the effect of MKIs on specifically the expression of non-constitutive proteasomes in cancer in general and in colorectal cancer in particular.…”

“…Indeed, considerably higher expression of immuno-proteasome subunits was shown in melanoma tissue infiltrated with CD3 + T-cells ( Woods et al, 2016 ). IFN-γ-induced stimulation of MHC I and immunoproteasome subunit expression was in turn augmented by MKIs in hepatocellular carcinoma cells ( Takahashi et al, 2021 ). Thus, treatment with such inhibitors affect generation and presentation of cancer antigens acting in a synergic manner with endogenous immune molecules and by this mean stimulate recognition of cancer cells by the immune system.…”

“…Except use of pro-inflammatory cytokines with pleiotropic effects, currently, no specific drugs that facilitate immunoproteasome synthesis are known. At the same time, several reports indicate altered immunoproteasome subunit expression following treatment of cancer cells with other types of anti-cancer drugs - protein kinase inhibitors that are currently widely used in clinical practice ( Burov et al, 2021 ; Takahashi et al, 2021 ).…”

HLA-A, HSPA5, IGFBP5 and PSMA2 Are Restriction Factors for Zika Virus Growth in Astrocytic Cells

“…Finally, ZIKV restores the expression of HLA-A in HLA-A KD U251 cells by 48 hpi; therefore, further experiments need to be conducted to better understand ZIKV infection. Moreover, the use of potential pharmaceutical compounds like MG132, a PSMA2 inhibitor known to exert anti-viral activity against HSV-1, trematinib which increases HLA-A expression via IFN gamma/STAT1 signaling and STAT3 activation and other tyrosine kinase inhibitors, need to be employed to identify novel anti-viral compounds against ZIKV infection [ 118 , 119 , 120 , 121 ]. The similarities and novelties of the current study in comparison to previously published omics studies help us understand some of the findings from this study better and further experiments need to be conducted to explain some of these differences and similarities across different cell types and omics platforms.…”