Scientists at Northwestern Medicine have discovered a biological marker that predicts which cancer patients are more resistant to immunotherapy. Dubbed USP22, the marker also points to a potential treatment target for non-responders. Findings published in The Journal of Clinical Investigation have the potential to transform care for patients whose current options remain limited.
Checkpoint blockade immunotherapy prevents harmful interactions between immune cells and cancer cells, keeping T-cells active so they can attack tumors. The approach has revolutionized cancer treatment over the past decade. However, despite early optimism about its potential to become a universal solution, immunotherapy only helps a small fraction of cancer patients.
Earlier research showed that low levels of MHC-I proteins on tumor cells contribute to treatment failure. These proteins normally flag abnormal cells for destruction by the immune system. Under healthy conditions, they display mutated proteins on cell surfaces that alert patrolling immune cells that something is wrong. Scientists didn’t understand why some cancers avoid this detection system and resist treatment even when everything else seems right.
Deyu Fang, a Hosmer Allen Johnson Professor of Pathology and senior study author, said restoring MHC-I protein function could reactivate the immune system against tumors. Understanding this process gives clinicians potential targets to pursue. The research team wanted to identify exactly what shuts down this critical alert system in resistant cancers.
Researchers examined lung tumor samples from patients before any treatment began. They identified a protein called USP22 as the culprit behind treatment resistance, especially when it occurs in high levels. USP22 reduces MHC-I levels on tumor surfaces and blocks the display of abnormal proteins that would normally trigger immune attacks throughout the tumor. Essentially, it acts like a cloaking device that hides cancer cells from immune surveillance.
The team tested this discovery in mice with lung, breast or colon tumors. They used genetic techniques and chemical compounds to suppress USP22 activity. Reducing this protein boosted immune activity throughout the tumors by increasing MHC-I presentation. Fang reported the intervention eliminated treatment resistance. Tumors were wiped out completely in all three cancer types tested, suggesting the findings could apply broadly across different cancers.
USP22 could serve as both a diagnostic tool and a treatment target for patients whose cancers resist immunotherapy. Analysis revealed nearly all resistant tumors showed consistently high USP22 levels. This pattern held true across different cancer types and patient groups. Blocking this protein might help currently unresponsive patients benefit from treatment, Fang suggested based on the experimental results. The discovery opens a new avenue for addressing one of immunotherapy’s biggest challenges.
Given the pace at which enterprises like Calidi Biotherapeutics Inc. (NYSE American: CLDI) are making progress in their research and development efforts aimed at advancing cancer immunotherapy, we can expect even more profound insights about why so few patients have been responding well to the existing immunotherapy options.
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