Good news! Impressive! Cancer is history (soon)! Seems to be a new, promising approach to look at the cellular waste processing!
Will this help to reduce resistance to immunotherapy? "[Only] About 20 to 40 percent of cancer patients currently respond to immunotherapy."
"... A study ... delved deep into the cellular source of antigens – the waste-processing machinery known as the proteasome – and pulled out a previously unknown mechanism that allows cancer cells to slip by immune system defenses. ...
the team applied these technologies to create the first-ever map of proteasome degradation activity in patient-derived tumor cells. ... “When we compared peptides derived from cancer cells with those from adjacent, noncancerous tissue, we noticed differences not only in the subset of proteins that were degraded, but also in the way they had been processed and cut.” This prompted the team to examine the proteasome from a new perspective: Rather than looking at the peptides it generates, they focused on the proteasome machinery itself. ...
the team applied these technologies to create the first-ever map of proteasome degradation activity in patient-derived tumor cells. ... “When we compared peptides derived from cancer cells with those from adjacent, noncancerous tissue, we noticed differences not only in the subset of proteins that were degraded, but also in the way they had been processed and cut.” This prompted the team to examine the proteasome from a new perspective: Rather than looking at the peptides it generates, they focused on the proteasome machinery itself. ...
Different types of proteasomes are mainly classified based on the specific enzymes within the barrel, and they specialize in different types of degradation. For example, the immunoproteasome excels at producing peptides ideally suited to becoming antigens. ... they noted an astonishingly large number of proteasomes that contained the protein PSME4. This protein, known as one of the regulatory “caps” making up the proteasome, was rarely found in proteasomes from adjacent, noncancerous tissues. ...
To test their theory, the team used online databases containing information about different cancers and patients’ responses to various treatments. In their search for a “proteasome fingerprint” characteristic of cancer cells, they were first of all surprised to discover just how notoriously heterogeneous the proteasome subunits in different types of cancer were. In addition, although the PSME4 protein was not enriched in all cancers, the databases clearly showed that patients whose cancers had high levels of PSME4 were less responsive to immunotherapy. ...
To make sure that PSME4 levels indeed directly affect the immune system, the researchers conducted a series of experiments involving mouse models of lung cancer. When mice were injected with cancer cells with reduced PSME4 expression, their immune systems were able to eliminate any signs of tumors. In contrast, injections of cancer cells with excessive PSME4 resulted in gigantic tumors and a negligible immune response. Finally, mice lacking any adaptive immune system were not affected by either an increase or a decrease in PSME4, which supported the idea that PSME4 levels affect the cancer by influencing the immune response. ..."
From the abstract:
"Immunotherapy revolutionized treatment options in cancer, yet the mechanisms underlying resistance in many patients remain poorly understood. Cellular proteasomes have been implicated in modulating antitumor immunity by regulating antigen processing, antigen presentation, inflammatory signaling and immune cell activation. However, whether and how proteasome complex heterogeneity may affect tumor progression and the response to immunotherapy has not been systematically examined. Here, we show that proteasome complex composition varies substantially across cancers and impacts tumor–immune interactions and the tumor microenvironment. Through profiling of the degradation landscape of patient-derived non-small-cell lung carcinoma samples, we find that the proteasome regulator PSME4 is upregulated in tumors, alters proteasome activity, attenuates presented antigenic diversity and associates with lack of response to immunotherapy. Collectively, our approach affords a paradigm by which proteasome composition heterogeneity and function should be examined across cancer types and targeted in the context of precision oncology."
The proteasome regulator PSME4 modulates proteasome activity and antigen diversity to abrogate antitumor immunity in NSCLC (no public access)
Tissues from mice transplanted with lung cancer cells. When PSME4 levels are high (left, top and bottom), the tumors grow bigger, cancer-fighting killer T cells (white) are reduced (top) and regulatory T cells (green) that inhibit the immune response are more abundant (bottom), compared with regular lung cancer cells (right, top and bottom)
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