Cancer cells release antioxidants to prevent immune cells from destroying them

Good news! Cancer is history (soon)! Are we finally cracking the secretes how cancer survives/counteracts immune responses and immunotherapy? 

"Now, scientists have discovered that certain immune cells depend on these very molecules to activate and destroy cancer cells, and that tumours exploit this dependency by releasing natural antioxidants to shut down the immune attack. ...

A team ... analysed the fluid surrounding cells within tumours grown in mice and found that cancers chemically ‘smother’ T cells, stopping their activation and preventing them from destroying cancer cells.

Tumours do this by releasing large amounts of a protein that is a natural antioxidant, Peroxiredoxin 1 (PRDX1), which mops up reactive oxygen species and deprives T cells of the activating signals they need to perform cancer killing.

Next, the team used CRISPR gene-editing technology to create mouse cancer cells that could no longer make the antioxidant protein. They found that removing the capacity for the cancer cells to produce the antioxidant promoted immune-cell activity and limited tumour growth. 

Finally, the team looked for the same mechanism in people. They analysed published data on the proteins released by human cancer cell lines, examined gene activity across thousands of human tumours, and isolated the fluid surrounding tumours removed from patients. All three approaches pointed the same way: human cancers also release PRDX1 into their surroundings, where it can strip away the reactive oxygen species that T cells depend on. ...

The findings also carry broader implications. Several large randomised clinical trials have found that antioxidant supplements fail to reduce cancer risk ..."

"New research reveals a promising new target for treating cancer by harnessing a type of molecule previously thought to do more harm than good.

For decades, reactive oxygen species, or ROS, often called free radicals, have been viewed primarily as harmful molecules linked to aging, DNA damage and cancer. A new study ... finds that cancer-fighting T cells need small amounts of ROS to attack tumors.

The investigators discovered that cancers exploit the T cell need for ROS by releasing an antioxidant protein that removes ROS from the tumor environment, effectively shutting down the attack by the immune system upon the cancer. ..."

From the editor's summary and abstract:

"Editor’s summary

Reactive oxygen species (ROS) have a paradoxical role in cancer.

Low to moderate ROS levels can stimulate tumor growth, whereas excessive ROS accumulation triggers oxidative stress and DNA damage.

Antioxidant therapies aim to neutralize free radicals and reduce oxidative stress, but clinical trials have not (yet) demonstrated improved cancer survival. Wesolowski et al. report that tumors can turn ROS dependency against the immune system, suppressing T cells and escaping antitumor immunity. 

Cancer cells secrete antioxidant enzymes, including peroxiredoxin 1 (PRDX1), into the extracellular space, depriving T cells of ROS needed for T cells to attack tumors effectively.

Removing PRDX1 from cancer cells restored antitumor immunity and made otherwise resistant tumors sensitive to checkpoint blockade immunotherapy.

These results suggest that targeting extracellular redox mechanisms could enhance the efficacy of immunotherapy.

Abstract

Reactive oxygen species (ROS) promote genomic instability and fuel oncogenic signaling in cancer, but antioxidant therapies have so far failed to improve, or worsen, cancer outcomes.

Emerging data suggest that T cells depend on ROS for signal transduction. 

In this study, we show that tumors exploit this dependency, releasing antioxidant enzymes into the tumor environment to suppress T cell–mediated antitumor immunity.

The interstitial fluid of tumors possesses potent antioxidant activity, associated with enrichment of the antioxidant enzyme peroxiredoxin 1 (PRDX1). Extracellular PRDX1 deprives T cells of ROS, preventing oxidative inactivation of phosphatases required for T cell receptor–driven kinase signaling and effector function.

Prdx1 is up-regulated upon cancer immunoediting, and loss of PRDX1 within tumors enhances antitumor immunity and immunotherapy responses.

These findings define a redox-dependent mechanism of tumor immunosuppression that is potentially amenable to therapeutic intervention."

Cancer cells release antioxidants to prevent immune cells from destroying them | University of Cambridge (original news release 1) "Molecules called reactive oxygen species, which include so-called 'free radicals', have long been viewed as damaging byproducts of our body’s metabolism – a reason why antioxidant supplements have been considered as a potential way of reducing cancer risk."

Cancer cells use antioxidant protein to suppress T cells, resist immunotherapy, study finds (original news release 2) "OHSU co-author helps identify potential therapeutic target in tumors that evade the immune system"

Tumor-derived antioxidants suppress immunity by depriving T cells of reactive oxygen species (no public access)

Killer T cells surrounding a cancer cell