The research, led by Professor Yifat Merbl of the Weizmann Institute of Science sheds light on the intricate world of cellular waste processing and its role in cancer’s ability to fly under the radar of our immune defenses. The team’s findings were recently published in the peer-reviewed Nature Cancer journal.

At the heart of this discovery lies the proteasome, the cellular machinery responsible for breaking down damaged or worn-out proteins into shorter protein chains known as peptides. These peptides play a critical role in shaping the cellular profile presented to the immune system. When these profiles appear suspicious, the immune system takes action to eliminate the potentially harmful cell.

Cancer, however, throws a wrench into this finely tuned system.

Regulatory processes in cancer cells become disrupted, increasing the chances of abnormal proteins being produced and presented as antigens on the cell’s surface. Despite their suspicious antigen profiles, the cancer cells manage to avoid immune detection.

Merbl’s team examined proteasome degradation activity in patient-derived tumor cells. Their work culminated in the creation of the first-ever map of proteasome degradation activity in these cells.

The research involved comparing peptides derived from cancer cells with those from adjacent noncancerous tissue. The researchers observed differences not only in the subset of degraded proteins but also in the processing and cutting of these peptides.

“We looked at the cancerous tissue and wondered – what is different about the structure of its proteasomes?” Merbl said.

They discovered a significant presence of the protein PSME4 within the proteasomes of cancerous tissues. PSME4, one of the regulatory “caps” that make up the proteasome, was rarely found in proteasomes from non-cancerous tissues. This finding led the team to delve deeper into the unique degradation style of PSME4-enriched proteasomes.

The analogy provided by the researchers is that different proteasomes are like chefs with distinct seasoning preferences. Some favor a “sour” flavor, while others create “sweeter” peptides more appealing to immune cells. The Weizmann team found that higher levels of PSME4 led to an increased production of sour peptides and a decreased quantity of sweet-flavored peptides.

This imbalance, the researchers said, makes it difficult for the immune system to accurately identify cancer cells, resulting in a compromised immune response.

The researchers hypothesized that elevated PSME4 levels in a tumor might diminish a patient’s response to immunotherapy, a treatment designed to enhance the immune system’s ability to combat cancer. To validate their theory, they turned to online databases containing information on various cancers and patients’ responses to treatments.

Their findings were striking. While proteasome subunits in different types of cancer exhibited significant heterogeneity, high levels of PSME4 were consistently associated with reduced responsiveness to immunotherapy. To further confirm the connection between PSME4 and immune response, the researchers conducted experiments with mouse models of lung cancer.

When mice received injections of cancer cells with reduced PSME4 expression, their immune systems efficiently eliminated the tumors. In contrast, injections of cancer cells with excessive PSME4 resulted in large tumors and a feeble immune response. Importantly, mice without an adaptive immune system were unaffected by changes in PSME4 levels, further reinforcing the link between PSME4 and the immune response.

“Our study focused on the proteasome in lung cancer, but our data indicate that there are other cancer types where PSME4 is abnormally abundant,” Merbl explained.

Merbl added that her lab is actively exploring the development of treatments that could reduce PSME4 levels in cancer — or block its binding to the proteasome — which would potentially render tumors more vulnerable to immunotherapy.