The checkpoint molecule CD47 has high hopes riding on it in oncology as being the innate immune equivalent of PD-1. Multiple companies are developing blockers against CD47 and/or its ligand, SIRPa, for the treatment of various tumors.
Now, investigators from Stanford University and the NIH have reported that CD47 signaling is active in the earliest phases of infectious disease, and that blocking it led to a more rapid immune response.
The results show that even the innate immune system, despite being the rapidly deployed first responder to infections, has check and balances built into it.
“All of us immunologists have been brought up thinking that when you get an infection, your first reaction is to get rid of that infection as quickly as possible,” Kim Hasenkrug told BioWorld. “But to make sure that doesn’t get out of control and cause something like… cytokine storm, [immunity] also puts this brake on” even at the earliest stages of infection.
“It takes a little while before the stimulatory effects predominate, and then you can mount a strong immune response,” he said. “If you take off that brake during the very earliest stages of an infection, you can get a much more rapid immune response.”
Hasenkrug is a senior investigator and chief of the retroviral immunology section of the National Institute of Allergy and Infectious Diseases’ Rocky Mountain Laboratories.
He is also a corresponding author of the paper describing the work, which was published online in mBio on June 23, 2020.
Hasenkrug’s co-corresponding author, Irving Weissman, is director of the Stanford Institute of Stem Cell Biology and Regenerative Medicine at Stanford University and co-founder, among other companies, of oncology company Forty Seven Inc.
Forty Seven was acquired by Gilead Sciences Inc. for $4.9 billion in March. The acquisition included magrolimab, a CD47-targeting antibody in clinical trials for several cancers, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL).
Earlier in 2020, Hasenkrug’s lab, with colleagues from the University Hospital Essen, had reported that blocking the interaction between CD47 and SIRPa increased the activity of antigen-presenting cells and sped up the clearance of lymphocytic choriomeningitis virus (LCMV) infections.
The work now published in mBio shows that CD47 signaling dampens innate immune activity pretty much whenever an infection occurs.
“Regardless of what sort of pathogen we infected cells with, the cells up-regulated CD47… which is curious, because CD47 is immunosuppressive,” Hasenkrug said.
“Virtually every pathogen will turn on this response,” he said, including the clinical giants hepatitis C virus and Mycobacterium tuberculosis.
“It’s exactly the opposite of what I expected,” he added. “We expected just a few pathogens to have a mimic.”
In principle, the results suggest that targeting the CD47-SIRPa axis could be used as a broad-spectrum anti-infective. CD47 up-regulation early in infection appears to be a universal or near-universal phenomenon, which means that targeting the process could be done without knowing the offending pathogen.
But Hasenkrug cautioned that for the time being, “we’re very cautious about using something like the CD47 blockade… there’s a reason that brake is there.”
He pointed to cytokine storms as a result of SARS-CoV-2 infections – COVID-19, he said with a hint of weariness, is “all we’re doing right now”— as an example of what can go wrong in the absence of a good brake.
On the other hand, it’s worth noting that immune system hyperactivity spells trouble when it comes relatively late during the course of an infection.
Checkpoint blockade, he said, could be dangerous “once the immune system is turned on.” But “people that mount a very rapid and strong immune response don’t even get sick.
“If we could catch these infections really early, we could use [checkpoint blockade] with anyone,” he said. “It’s going to be about timing.”
Another possible use of CD47 blockade is to enhance vaccine effectiveness.
Along with almost everything else in the body, the immune response weakens with age, a phenomenon known as immunosenescence.
Speaking again of SARS-CoV-2, Hasenkrug said that “the vaccines that are coming out… might not work as well in older people, [or] they might not work at all in older people.”
Turbocharging the innate immune system could ultimately lead to stronger immunity in response to vaccines, even though it has no direct effect on the memory B and T cells that are responsible for lasting immunity, be it due to vaccination or infection.
But those B and T cells are activated by innate immune signaling, and so “by dampening the early response,” Hasenkrug said, CD47 signaling is “also dampening the downstream response.”