The mechanism of resistance developed by cancer cells against immunotherapy has been discovered

Immunotherapies are revolutionizing modern cancer treatment. The aim of immunotherapies is to prevent the immune system from being “perceived as friendly” by cancer cells. However, immunotherapies were not producing the expected results in some patients. Cancer Discoverypublished a study showing that mutations in certain genes determine the response to immunotherapy.

Immunotherapies are fundamentally based on disrupting the interaction between the proteins PD1 and PD-L1. The 10 hallmarks of a cancer cellinclude the ability to become invisible to the immune system. Cancer cells achieve this by carrying the “PDL-1” receptor on their surface, which makes immune system cells perceive them as friendly. The “PD1” protein on immune system cells thus binds to “PD-L1”, making the cancer cell appear “friendly”. Pembrolizumab, an immune checkpoint inhibitor (immune checkpoint inhibitors = immune checkpoint regulators), aims to prevent this binding. Pembrolizumabproduced good results, but success was very limited in some patients. With the support of genetic science, researchers tried to understand why by analyzing patients’ tumor samples during and after immunotherapy.

According to the research results:

• Mutations in the JAK1 / JAK 2 genes in tumor cells were found to cause the PD-L1 protein to be inactive. Patients whose tumors contained mutations in the JAK1/JAK2 genes were found not to respond to immunotherapy.

It must be emphasized that JAK genes participate in pathways that enable cancer cells to recognize the immune system. T cells, which are immune system cells, secrete a molecule called interferon gamma to try to recognize cancer cells. These immunotherapies primarily aim to use anti-PD1 or anti-PD-L1 antibodies to enable T cells to recognize cancer cells specifically and release interferon gamma against them. Interferon gamma is very important in generating an immune response against cancer. To cope with this, cancer cells subjected their interferon gamma signaling pathways to mutation , preventing attacks by T cells activated after immunotherapy. In this way, primary resistance to immunotherapy developed by keeping both PD-L1 expression and interferon signaling pathways inactive.

What does this study mean clinically?

• Genetic analyses can identify the relevant mutations, allowing selection of the patient group most suitable for immunotherapy.
• Elucidating immunotherapy resistance is highly important for developing inhibitors against proteins involved in resistance to immunotherapy.