The integrated stress response promotes B7H6 expression

Akram Obiedat, Yoav Charpak-Amikam, Julie Tai-Schmiedel, Einat Seidel, Mohamed Mahameed, Tony Avril, Noam Stern-Ginossar, Lorraine Springuel, Jennifer Bolsée, David E. Gilham, Priya Dipta, Miriam Shmuel, Eric Chevet, Ofer Mandelboim, Boaz Tirosh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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 CAR-T cells directed against B7H6. Our study highlights a novel mechanism to induce B7H6 expression and suggests a pharmacological approach to improve B7H6-directed immunotherapy. Key messages: B7H6 is induced by ER stress in a PERK-dependent mechanism.Induction of B7H6 is obtained pharmacologically by HIV protease inhibitors.Exposure of tumor cells to the HIV protease inhibitor nelfinavir improves the recognition by B7H6-directed CAR-T.

Original languageAmerican English
Pages (from-to)135-148
Number of pages14
JournalJournal of Molecular Medicine
Volume98
Issue number1
DOIs
StatePublished - 1 Jan 2020

Bibliographical note

Funding Information:
Research was funded by grants from the David R. Bloom Center for Pharmacy, the Dr. Adolph and Klara Brettler Center for Research in Pharmacology, Israeli Cancer Association and the Israel Science Foundation (grant no. 696/14) to BT. BT and EC were supported by a grant from the Ministry of Science & Technology, Israel and The Ministry of Europe and Foreign Affairs, France and the Ministry of Higher Education, Research and Innovation, France. PD is a Marie Curie fellow (Treatment H2020-MSCA-ITN-721236).

Publisher Copyright:
© 2020, The Author(s).

Keywords

  • B7H6
  • CAR-T
  • PERK
  • UPR

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