The integrated stress response promotes B7H6 expression

Abstract

The B7 family member, B7H6, is a ligand for the natural killer cell receptor NKp30. B7H6 is hardly expressed on normal tissues, but undergoes upregulation on different types of tumors, implicating it as an attractive target for cancer immunotherapy. The molecular mechanisms that control B7H6 expression are poorly understood. We report that in contrast to other NK cell ligands, endoplasmic reticulum (ER) stress upregulates B7H6 mRNA levels and surface expression. B7H6 induction by ER stress requires protein kinase R-like ER kinase (PERK), one of the three canonical sensors of the unfolded protein response. PERK phosphorylates eIF2α, which regulates protein synthesis and gene expression. Because eIF2α is phosphorylated by several kinases following different stress conditions, the program downstream to eIF2α phosphorylation is called the integrated stress response (ISR). Several drugs were reported to promote the ISR. Nelfinavir and lopinavir, two clinically approved HIV protease inhibitors, promote eIF2α phosphorylation by different mechanisms. We show that nelfinavir and lopinavir sustainably instigate B7H6 expression at their pharmacologically relevant concentrations. As such, ER stress and ISR conditions sensitize melanoma targets to CART cells directed against B7H6. Our study highlights a novel mechanism to induce B7H6 expression and suggests a pharmacological approach to improve B7H6-directed immunotherapy.

Targeting the Integrated Stress Response in Cancer Therapy

“…It was reported that ISR promotes the expression of potential target for immunotherapy (Obiedat et al, 2020). Thus, ISR may play a role in cancer immunotherapy.…”

“…BTdCPU and ONC201 activates HRI (Kline et al, 2016;Chen et al, 2011). Bortezomib, gemcitabine, lopinavir and CCT020312 selectively activates PERK (Narita et al, 2015;Palam et al, 2015;Obeng et al, 2006;Obiedat et al, 2020;Stockwell et al, 2012). BEPP works on PKR activation (Figure 3) (Hu et al, 2009).…”

Nelfinavir Inhibition of Kaposi’s sarcoma-associated herpesvirus protein expression and capsid assembly

“…These different observations of how nel navir inhibits herpesvirus production could be related to the differences in how the two viruses replicate and the optimal cell culture system that each virus is grown in. We believe, for KSHV it is the effect of the drug on the ISR [24,34] which then manifests as a block in virus capsid assembly. This was evident in the viral protein analysis which showed that the accumulation of some KSHV proteins was inhibited by nel navir.…”

Bromodomain protein BRD4 is an epigenetic activator of B7-H6 expression in acute myeloid leukemia

“…[1][2][3] However, during malignant transformation B7-H6 expression increases due to the activation of endoplasmic reticulum stress, oncogenes such as MYC, or epigenetic mechanisms. [4][5][6][7] B7-H6 was first identified as a ligand of NKp30/NCR3, an activating receptor of NK cells that triggers cytotoxicity and cytokine secretion acting against tumor cells. 8 However, in recent years it has been shown that B7-H6 has a non-immunological role in tumorigenesis because it can inhibit apoptosis and promote the proliferation of tumor cells.…”