Immunotherapy is a method of treating cancer by reprogramming the immune system of patients to attack their tumors. This cutting-edge treatment has had a significant impact on the treatment of cancer patients, and there have been cases of long-term remission.

 

However, many patients either do not respond to immunotherapy, or even if they do, the effect is temporary, which highlights how important it is for us to better understand the mechanism that causes cancer to resist this treatment.

 

In a new study, researchers from the Federal Institute of Technology in Lausanne, the University Hospital of Lausanne, the Swiss Institute of Bioinformatics, the Ludwig Cancer Institute and Roche found a way to break the resistance of neuroendocrine pancreatic cancer mice to immunotherapy. This kind of cancer is highly resistant to immunotherapy called immune checkpoint blocking. In this immunotherapy, patients receive a drug (immune checkpoint inhibitor). This drug blocking usually makes the immune response not too strong, but also can prevent immune cells (T cells) from killing the protein of cancer cells. Relevant research results were published in the journal of Immunity, with the title “Specific PD1-IL2v and anti-PD-L1 break tube immunity resistance by enhancing stem-like tumor-reactive CD8+T cells and reprogramming mechanisms”.

 

 

These authors evaluated an engineered protein-antibody fusion called immunocytokine, which is increasingly used in immunotherapy. They focus on the bispecific immune cytokine PD1-IL2v, which is newly developed by Roche and can target tumors, where it activates killer T cells to attack cancer cells that drive tumor growth.

 

These authors combined the immune cytokine PD1-IL2v with the immune checkpoint inhibitor anti-PD-L1, thus enhancing the anti-tumor immune response to immunotherapy-resistant tumors. They wrote, “[PD1-IL2v] is even more effective when combined with anti-PD-L1, an immune checkpoint inhibitor. Compared with traditional anti-PD-1 therapy, PD1-IL2v induces stronger and more specific expansion of anti-tumor T cells by stimulating specific T cell subtypes, while anti-PD-L1 targets and destroys the barriers established in the tumor microenvironment, namely, tumor-promoting macrophages and tumor blood vessels, which jointly resist anti-tumor immunity.”

 

The combination of these two molecules improves the survival rate of tumor-bearing mice, and produces a more lasting therapeutic effect than the simple bispecific immune cytokine itself. By reprogramming immunosuppressive tumor-related macrophages and tumor blood vessels, this combination makes cancer easier to be detected by immune cells, thus improving the therapeutic effect.

 

Douglas Hanahan of the Federal Institute of Technology in Lausanne, the co-author of the paper, said that “This innovative immunotherapy combination makes PD-1+stem-like T cells infiltrated our immunotherapy resists tumor sensitization and leads to tumor destruction, thus bringing survival benefits. Recently, scientists have found that PD-1+stem cell-like T cells are important for maintaining effective anti-tumor immune responses. These exciting results provide the basis for clinical trials aimed at evaluating the combined treatment of PD1-IL2v and anti-PD-L1, which may have been initially carried out in immunotherapy-resistant cancer patients with T-cell infiltrating tumors.”

 

Reference

Mélanie Tichet et al. Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor-reactive CD8+ T cells and reprogramming macrophages. Immunity, 2023, doi:10.1016/j.immuni.2022.12.006.