Tumors adapt to their environment to avoid detection. As different cancer treatments progress, tumors mutate and become resistant. Various markers are expressed on tumors that can be used to target in cancer therapy. However, a lot of these markers can also be expressed on healthy tissues. Treatments that target markers on both tumors and healthy cells result in off-target affects. Some therapies have been developed to target markers specifically on tumor cells, which avoid adverse side effects in patients. Unfortunately, tumors tend to progress and shed that targeted marker, which limit therapeutic efficacy. The tumor is complex, and each cell is different than the other, making it hard to treat. Therefore, researchers combine therapies to target different aspects of tumor growth and development. Specifically, chemotherapy is used in combination with immunotherapy, small molecule inhibitors, and/or surgery. Researchers have started combining various therapies to overcome tumor progression. As a result, scientists are working to eliminate ‘tumor immune escape’ by investigating intratumoral mechanisms.
A recent article in Immunity, by Dr. Xuetao Cao and others, reported that inhibiting an enzyme in the cancer cells can sensitize tumors to immunotherapies. This enzyme is directly involved in cell metabolism, or the process in which it generates energy. By inhibiting this enzyme, the cancer cells lose the ability to divide rapidly. Consequently, this work has major implications on cancer treatment and has the potential to improve standard-of-care therapy.
Cao is a Professor of Immunology and Director of the Institute of Basic Medical Sciences in the Chinese Academy of Medical Sciences, Beijing, China. Cao is an internationally renowned scientist and is known for his work on innate immunity and tumor immunology. His group has identified several immune cell subsets and 22 novel molecules that are involved in immune response. He is a pioneer in cancer immunotherapy and has worked to get various immunotherapies approved by the Chinese Food and Drug Administration (FDA). His current work focuses on improving cancer immunotherapy in solid tumors.
Cao and his group identified dihydroorotate dehydrogenase (DHODH) as a possible target to sensitize tumors to immunotherapy. DHODH is a key enzyme in the process of generating deoxyribonucleic acid (DNA) and is upregulated in proliferative cells, such as tumors. Therefore, researchers blocked this enzyme and found that not only did tumor growth slow down, but tumors expressed key surface markers that allowed the immune system to recognize and target the cells.
The team studied various solid tumors, including triple negative breast cancer (TNBC), which are all resistant to an immunotherapy called ‘anti-PD-1’. This immunotherapy targets specific markers on immune cells to allow them to recognize cancer. Interestingly, Cao and his team paired DHODH inhibition treatment with anti-PD-1 and found that DHODH inhibition reverses therapy resistance.
Cao and others discovered a novel mechanism that sensitizes tumor susceptibility to cancer treatments. Moreover, this inhibitory mechanism allows for immunotherapies to overcome tumor resistance. These findings are paradigm-shifting and offer novel insight into how physicians should target solid tumors moving forward. As a result, this report has the potential to improve current standard-of-care therapies and prolong patient survival.
Article, Immunity, Xuetao Cao, Chinese Academy of Medical Sciences
