Inhibition of QPCTL Induces Myeloid Immune Checkpoint Blockade

Immune checkpoint therapies targeting inhibitory checkpoint molecules such as PD-1 and CTLA4 have been developed to activate antitumor T-cell responses. Similar therapies are under development for myeloid cells such as macrophages and neutrophils that are also regulated by stimulatory and inhibitory signals. For example, CD47 expressed on tumor cells binds to SIRPα expressed on myeloid cells to activate a “don't eat me”' signal. Myeloid checkpoint blockade can be achieved by targeting the CD47-SIRPα axis using anti-CD47 antibodies in combination with tumor-opsonizing antibodies that enhance phagocytosis. To identify modulators of CD47 binding to SIRPα that could serve as potential targets for myeloid cell checkpoint blockade, Logtenberg and colleagues performed a FACS-based haploid genetic screen to look for gene mutations that reduce the binding of anti-CD47 antibody to the SIRPα recognition site. This screen revealed glutaminyl-peptide cyclotransferase-like (QPCTL) protein as a modulator of CD47–SIRPα binding. QPCTL is an enzyme that catalyzes the cyclization of N-terminal glutamine and glutamic acid residues into an N-terminal pyroglutamate residue (pGlu). Knockout of QPCTL selectively inhibited the binding of recombinant SIRPα and anti-CD47 antibody specific to the SIRPα binding site. Pyroglutamate formation on CD47 was associated with QPCTL expression and occurred early in the CD47 protein life cycle. Treatment with QPCTL inhibitors resulted in significant reduction of pGlu-CD47 formation without affecting surface levels of CD47. In addition, inhibition of pGlu formation enhanced the antitumor activity of myeloid cells similarly to antibody blockade of CD47 or SIRPα, and deletion of QPCTL controlled in vivo tumor growth to a similar extent as CD47 deletion. Lastly, both inhibition and deletion of QPCTL synergized with anti-EGFR or anti-HER2 antibodies to induce neutrophil-mediated tumor killing. Collectively, these results describe QPCTL as a modifier of the CD47–SIRPα checkpoint that can be targeted to facilitate immune checkpoint blockade of myeloid-derived antitumor responses.

Logtenberg ME, Jansen JH, Raaben M, Toebes M, Franke K, Brandsma AM, et al. Glutaminyl cyclase is an enzymatic modifier of the CD47-SIRPα axis and a target for cancer immunotherapy. Nat Med 2019 Mar 4 [Epub ahead of print].

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