Phosphoinositide 3-Kinase Signaling Can Modulate MHC Class I and II Expression

Abstract

Molecular events activating the PI3K pathway are frequently detected in human tumors and the activation of PI3K signaling alters numerous cellular processes including tumor cell proliferation, survival, and motility. More recent studies have highlighted the impact of PI3K signaling on the cellular response to interferons and other immunologic processes relevant to antitumor immunity. Given the ability of IFNg to regulate antigen processing and presentation and the pivotal role of MHC class I (MHCI) and II (MHCII) expression in T-cell-mediated antitumor immunity, we sought to determine the impact of PI3K signaling on MHCI and MHCII induction by IFNg. We found that the induction of cell surface MHCI and MHCII molecules by IFNg is enhanced by the clinical grade PI3K inhibitors dactolisib and pictilisib. We also found that PI3K inhibition increases STAT1 protein levels following IFNg treatment and increases accessibility at genomic STAT1-binding motifs. Conversely, we found that pharmacologic activation of PI3K signaling can repress the induction of MHCI and MHCII molecules by IFNg, and likewise, the loss of PTEN attenuates the induction of MHCI, MHCII, and STAT1 by IFNg. Consistent with these in vitro studies, we found that within human head and neck squamous cell carcinomas, intratumoral regions with high phospho-AKT IHC staining had reduced MHCI IHC staining.Implications: Collectively, these findings demonstrate that MHC expression can be modulated by PI3K signaling and suggest that activation of PI3K signaling may promote immune escape via effects on antigen presentation.

Immunomodulation by targeted anticancer agents

“…Of note, while PI3K and AKT1 inhibitors have also been shown to boost IFNG-driven class I and class II antigen presentation as a mechanism of cancer-cell-dependent immunostimulation (Chandrasekaran et al, 2019;Marijt et al, 2019;Sivaram et al, 2019), MTOR inhibitors are not expected to mediate a similar activity, largely reflecting the notions that these agents potently activate autophagy (Galluzzi et al, 2017a) and that autophagy limits MHC class I levels on the surface of malignant cells (Yamamoto et al, 2020). Moreover, autophagy is a potent inhibitor of type I IFN secretion by breast cancer cells responding to radiation (Rodriguez-Ruiz et al, 2019;Yamazaki et al, 2020), implying that caution should be taken when combining MTOR inhibitors with radiotherapy.…”

Deregulation of HLA-I in cancer and its central importance for immunotherapy

“…93 Pharmacological inhibition of PI3K restored IFNγ/STAT1 signaling transduction and surface class I HLA expression in vitro. 93 129 A study by Sivaram et al investigating the impact of mutational activation of PI3K in an orthotopic pancreas mouse model showed that inhibition of the PI3K pathway increases MHC-I expression, leading to tumor regression due to T cell infiltration. 130 Importantly TCGA database analysis also reveals a negative correlation between activated PI3K-Akt and HLA-I-mediated regression in head and neck cancer, lung squamous carcinoma, and pancreatic adenocarcinoma.…”

Strategies to Overcome Failures in T-Cell Immunotherapies by Targeting PI3K-δ and –γ

“…We have previously linked PI3K pathway signaling to tumor antigen presentation mechanisms in head and neck cancers. PTEN loss and PI3K activation downregulated major histocompatibility complex (MHC) Class I and Class II induction by IFN-g, and clinical tumor samples demonstrated inverse staining associations of MHC and Phospho-S6, a serine/ threonine kinase downstream of PI3K (106). Downregulation of MHC expression in HNSCC and melanoma has a clinical correlation with treatment resistance and poorer clinical outcomes (102)(103)(104).…”