TAU researchers take on battle vs immunotherapy-resistant tumors

Numerous medical and scientific discoveries have been made accidentally. They include X-rays, penicillin, Viagra, radioactivity, pacemakers, microwaves, nitrous oxide (laughing gas), and the blood thinner Warfarin. Some researchers claim that a third to half of all scientific discoveries were not planned.

Now, researchers at Tel Aviv University (TAU) can add to that list their important discovery of a cancer mechanism that has been shown to prevent the immune system from attacking tumors. In a very detailed study published in the prestigious journal Nature Communications under the title “Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy,” the team announced their serendipitous breakthrough. The team included Prof. Carmit Levy, Prof. Yaron Carmi, and doctoral student Avishai Maliah in the Faculty of Medical and Health Sciences.

The researchers were amazed to discover that reversing this mechanism stimulates the immune system to fight the cancer cells – even in types of cancer considered resistant to dominant forms of immunotherapy.

It all happened by coincidence, Levy recalled. “My lab studies both cancer and the effects of ultraviolet (UV) radiation from the sun on our skin and body, both of which are known to suppress the immune system. For more than 3,500 years, sunlight has been used as a treatment for autoimmune skin diseases like psoriasis and vitiligo (a skin disorder that makes it lose pigmentation or color).

“About 30 years ago, it was discovered that ultraviolet radiation B (UVB) inhibits the immune response to cancer in mice. The scientists hypothesized that using UVB, which inhibits autoimmunity as well as the immune response to cancer, could serve as a platform for investigating the regulation of the immune response to cancer, possibly leading to the identification of factors that could be targeted for the development of new oncological treatments.

“The cancer suppresses approaching immune cells,” Levy continued, “while solar radiation represses the skin’s immune system. While in most cases, we cancer researchers worldwide focus on the tumor and look for mechanisms by which cancer inhibits the immune system, here we proposed a different approach – investigating how UV exposure subdues the immune system and applying our findings to cancer. The discovery of a mechanism that inhibits the immune system opens new paths for innovative therapies.”

Protein to enhance immunotherapy

With this idea in mind, Levy asked Carmi, who is a world expert on the immune system, to join the research, and Maliah led the project. Using a mouse model, the first stage was a thorough investigation of changes in the mice with subcutaneous melanoma (below the skin). They were not responsive to anti-PD1 immunotherapy following chronic UV irradiation, to which they were exposed before injection of the tumor because of the suppression of T-cell killing ability in skin-draining lymph nodes.

The doctoral students examined the behavior of dozens of proteins after being exposed to UV, and they were amazed to see a significant rise in the level of a relatively unexplored protein called Ly6a. 

This unexpected finding led the team to delve deeper to understand the protein function and whether it’s involved in the immune-suppression process.

The researchers were surprised to discover that this protein, Ly6a, is also over-expressed in cancer tumors – apparently inhibiting T cells, said Levy. “Having found this in two types of cancer – melanoma skin cancer and colon cancer– we have reason to believe that the same thing happens in other cancers as well. Evidently, we have discovered a general mechanism through which cancer tumors desensitize the immune system. 

Cancer was treated with Ly6a antibodies, and amazingly, the tumors were significantly reduced. In addition, cancers resistant to known treatments reacted substantially to Ly6a antibodies.”

The discovery can have practical implications in immunotherapy – treating cancer by enhancing the response of the immune system, the team suggested.