A Step Forward in Cancer Treatment: How a New Mechanism Could Overcome Immunotherapy Resistance

Approximately 3 decades ago, it was found that UVB suppresses the immune response to cancer in mice. It was suggested that UVB shows this effect due to changes in the phenotypes of certain types of immune cells. According to Prof. Levy, “My lab examines cancer and ultraviolet (UV) radiation from the sun that acts on the skin and most of the human body both of which, cancer and UV rays, are immunosuppressive”. Cancer shields the immune cells from reaching the site, while solar radiation shields the skin from responding to invading pathogens. The paper was published in Nature Communications.

While in most cases, cancer researchers worldwide focus on the tumour and look for mechanisms by which cancer inhibits the immune system, they proposed a different approach: exploring how UV exposure dampens immune response and extrapolating from it as applied to cancer. The finding of the anti-immune system as a phenomenon paves the way for more creation of different types of therapies. 

Avishai looked at the changes in the activity of dozens of proteins after the UV treatment and was surprised to find that the level of a less studied protein called Ly6a had gone up significantly. They have found this, which prompted them to carry out further research to know more about the protein function and to know whether the protein is correlated to the immune suppression process. 

Our natural immune system can respond rapidly and tremendously effectively, but it has numerous safeguards and regulators to ensure that it is not overstimulated and thus becomes auto immune, meaning it attacks parts of the body’s tissues. 

When our skin is exposed to UV radiation from the sun, our immune system responds immediately: blood vessels dilate, DNA is mended wherever potential, and cells carrying mutations are seen and pulled out. At the same time, a strong control system with a large number of brakes is also launched to minimize activity. 

As Prof. Levy notes, “The use of sunlight to control autoimmune diseases of the skin that occur when the skin’s immune system becomes overactive is well understood.” 

Avishai Maliah adds, “Our study showed that exposure to UV radiation causes T cells of the immune system responsible for fighting cancer to produce high amounts of Ly6a protein.” He thought that perhaps Ly6a is a brake that UV uses to control the immune system, and it might allow UV to release this brake, and therefore, the immune system can be optimally activated once again. 

Having said that, Prof. Levy notes, “We were quite shocked to learn that this protein is overproduced in cancer tumours and seems to suppress T cells.” Since they have witnessed this in two types of cancer, melanoma skin cancer and colon cancer, they supposed the same thing to be true in other cancers. 

Researchers have found a broad strategy for how cancer tumours create immunosuppression. On Ly6a antibodies, Avishai administered treatment for cancer, and to his surprise, the tumours shrank. In addition, cancers that did not respond to identified therapies responded to a significant extent to Ly6a antibodies. 

This new finding can have a significant application in immunotherapy-treatment of cancer through the stimulation of the immune system. 

Prof. Carmi sums up his presentation, “Immunotherapy has changed the outlook of handling cancer.” However, approximately half of the patients do not react to the present dominant therapy-the protein PD1. Researchers team identified Ly6a protein and subsequently identified the antibody of Ly6a to eliminate tumours not only in the PD1-treated naive animals but also in the tumour-resistant population of model animals. Currently, they are trying to apply these results to human cancer patients and develop a new effective treatment. 

Reference: Maliah A, Santana-Magal N, Parikh S, Gordon S, Reshef K, Sade Y, et al. Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy. Nature Communications