Together with an international research team, DZL scientist Prof. Dr. Silke Meiners studied lung carcinomas and found that the proteasome regulator PSME4 is upregulated in these tumors. Her scientific findings show a link between cellular proteasome activity and a lack of response to immunotherapy in the treatment of lung cancer.
DZL scientist Prof. Dr. Silke Meiners, together with Prof. Yifat Merbl of the Weizmann Institute of Science, Israel, and an international research team, published a study that investigated the relationship between the molecular composition of the proteasome complex and response to immunotherapy in cancer patients. To do this, the researchers reviewed samples from hundreds of patients with bladder, lung, melanoma, and kidney cancers and found that proteasome composition can vary widely in different types of cancer as well as between different patients.
Immunotherapy is a method that uses the body's own immune system to fight tumors. It has revolutionized treatment options for cancer. However, not all patients respond to the drugs used and cancer cells can develop resistance, allowing them to escape destruction by the immune system despite therapy. The mechanisms underlying resistance in many patients remain poorly understood. For this reason, the team led by Silke Meiners has been investigating whether and how differences in the proteasome complex in different patients affect tumor progression and response to immunotherapy.
The human immune system not only protects us from infections, but also has functions that protect us from cancer. The so-called proteasomes are involved in these mechanisms. These are cellular complexes that are responsible for the degradation of proteins within the cell. In addition, proteasomes are involved in antigen processing, antigen presentation, inflammatory signaling, and immune cell activation. The researchers were able to show that the composition of the proteasome complex varies greatly in different types of cancer and affects the interactions between the tumor and the immune system as well as the tumor microenvironment, i.e., the immediate environment of a tumor. By degradation profiling non-small cell lung cancer samples from patients, scientists have found that the proteasome regulator PSME4 is upregulated in tumors. This alters proteasome activity and attenuates the antigen diversity presented, which is associated with a lack of response to immunotherapy.
In conclusion, proteasome diversity between different patients and in different cancers can be considered an important factor determining tumor immunity and individual response to immunotherapy. A better understanding of this diversity is of clinical importance, as this knowledge can help precision oncology target cancer vulnerabilities and improve the targeted effect of immunotherapy.
Javitt A, Shmueli MD, Kramer MP, Kolodziejczyk AA, Cohen IJ, Radomir L, Sheban D, Kamer I, Litchfield K, Bab-Dinitz E, Zadok O, Neiens V, Ulman A, Wolf-Levy H, Eisenberg-Lerner A, Kacen A, Alon M, Rêgo AT, Stacher-Priehse E, Lindner M, Koch I, Bar J, Swanton C, Samuels Y, Levin Y, da Fonseca PCA, Elinav E, Friedman N, Meiners S, Merbl Y. The proteasome regulator PSME4 modulates proteasome activity and antigen diversity to abrogate antitumor immunity in NSCLC. Nat Cancer. 2023 May;4(5):629-647. doi: 10.1038/s43018-023-00557-4. epub 2023 May 22. PMID: 37217651.