Blocking Cancer Antioxidant Protein May Help Immunotherapy Work Better

A team of researchers have discovered a new method by which cancer cells evade the immune system. If further studies confirm their findings, this might cause another approach for optimizing cancer immunotherapy. Scientists from the University of Cambridge and Oregon Health & Science University have shown that tumors secrete an antioxidant protein, peroxiredoxin 1 (PRDX1), which inhibits T cells capable of fighting the cancer by preventing them from getting the signals they need to do their job. The study appeared in Science on 3 September.

This finding means that the popular conception of antioxidants being good in the body may not be correct. You hear about the damage the reactive oxygen species (also called ROS or free radicals) do with causing damage as well as cancer; but, the latest study shows that if there are small quantities ROS can activate T cells which are what attack and kill abnormal cells.

That means, researchers discovered that cancer cells can take advantage of this biological need. Tumors secrete PRDX1 into the fluid around the cancer cells, which scavenges ROS from the local microenvironment. This alters the chemistry of the environment and prevents T cells from becoming fully activated and sustaining their anti-cancer response.

They categorized this process as some form of redox checkpoint. It is unlike other less familiar immune checkpoints, like the PD-1 and PD-L1 systems targeted by many cancer drugs, in that it works via the chemical environment around the tumorand that may be the reason certain cancers persist in their immunotherapy resistance even after existing checkpoint inhibitors have been attempted.

We have explored its function by turning off the genes that make this antioxidant protein in cancer cells using CRISPR gene editing. This had remarkable effects in various cancer models. Ablation of this antioxidant increased immune responses, halting tumor progression. For one melanoma model, cells without PRDX1 were too weak to be tolerated by the host, and were cleared in a spontaneous rejection. For other tumors, expression of this protein conferred resistance to immune therapy.

And, the researchers asked if their mechanism could be applicable for human malignancies. They analyzed human cancer cell lines and several thousand tumor samples, as well as fluid off tumors of patients, which gathered information that suggests the secretion and elevated activity level of PRDX1 could take place during this process but the work does not yet show that inhibiting PRDX1 will be beneficial to patients.

The therapy concept itself is fairly simple in structure, in that if the cancerous cells are relying on the protein to take away the ROS they need from the T cell, then inhibiting that could standardise the chemical environment to allow the correct functioning of immune cells. [Researchers] believe that inhibiting or blocking the translocation of PRDX1 can be a future treatment for cancer cells, perhaps used in tandem with other forms of immunotherapy.

Though it might future development of PRDX1 as a treatment, there is still much work to be done before this can be trialled as a standard treatment. Much of what we currently know about PRDX1 is preclinical, derived from lab and cancer models or analysis of human biological data. There is no current clinical evidence to suggest that a PRDX1-blocking drug with benefit survival or treatment response in cancer patients.