Deciphering regulatory principles of proteasome heterogeneity and the degradation landscape in cancer

Project Information

Cancer_Deg

Grant agreement ID: 101045613

DOI

10.3030/101045613

EC signature date 25 July 2022

Start date 1 August 2022

End date 31 December 2027

Funded under

• European Research Council (ERC)

Total cost

€ 1 978 750,00

EU contribution

€ 1 978 750,00

Coordinated by

WEIZMANN INSTITUTE OF SCIENCE
Israel

Periodic Reporting for period 1 - Cancer_Deg (Deciphering regulatory principles of proteasome heterogeneity and the degradation landscape in cancer)

Reporting period: 2022-08-01 to 2025-01-31

Summary of the context and overall objectives of the project

Proteasome activity plays a vital role in the body by breaking down and removing defective or unneeded proteins. It also helps regulate the immune system's ability to recognize harmful cells. In cancer, proteasomes play a key role in how tumors grow, how the immune system detects them, and how they respond to treatments like immunotherapy. However, a complete understanding of how proteasomes vary between patients and their role in cancer is still lacking.
Our innovative method, MAPP (MS Analysis of Proteasome-cleaved Peptides), is designed to fill this gap. We've already shown that it can identify important processes in cancer, such as changes in protein breakdown related to inflammation and the role of specific proteasome subunits, like PSME4, in reducing inflammation in lung cancer.
With this project, we aim to build on our findings and expand MAPP’s capabilities to uncover more about how proteasomes function in cancer. Specifically, we plan to analyze the makeup of proteasomes and the protein degradation patterns across different cancer types. Our goal is to create a comprehensive picture of how proteasomes influence the immune response to tumors and their response to immunotherapy in different patients. This research will transform our understanding of protein degradation in cancer, offering new insights for precision oncology and drug discovery.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Our work examines the role of proteasomal degradation—a process that breaks down proteins—as it relates to tumor antigen presentation, which is essential for immune recognition of cancer cells. Utilizing a method we developed in the lab, called MAPP (Mass Spectrometry Analysis of Proteasomally-Cleaved Peptides), we captured these degradation products and revealed how tumors, like non-small cell lung cancer (NSCLC), alter protein breakdown to avoid immune detection. These findings, recently published, suggest that targeting PSME4 could enhance immune recognition of cancer. We are now expanding our approach to examined the degradation landscape in other cancer types to uncover whether and how proteasomal degradation may be involved in shaping tumor inflammation, progression and the response to immunotherapy.
In another line of research, stemming from the MAPP technology, we found that cellular proteasomes may have an unappreciated role in innate immunity. Once confirmed, it suggest we may have a pool of naturally-cleaved antimicrobial peptides that may serve to combat antibiotic resistance. This will require to generate some computational models for predicting the potency ofOur work examines the role of proteasomal degradation—a process that breaks down proteins—as it relates to tumor antigen presentation, which is essential for immune recognition of cancer cells. Utilizing a method we developed in the lab, called MAPP (Mass Spectrometry Analysis of Proteasomally-Cleaved Peptides), we captured these degradation products and revealed how tumors, like non-small cell lung cancer (NSCLC), alter protein breakdown to avoid immune detection. These findings, recently published, suggest that targeting PSME4 could enhance immune recognition of cancer. We are now expanding our approach to examined the degradation landscape in other cancer types to uncover whether and how proteasomal degradation may be involved in shaping tumor inflammation, progression and the response to immunotherapy. such peptides prior to testing their role in vitro and in vivo.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Our work on PSME4 identified a novel role for intra-tumoral proteasomes in shaping the tumor microenvironment and the response to immunotherapy. Notably, it suggests that proteasome composition may be a critical component in assessing the potential response, independent from the tumor mutational burden. This knowledge is currently not considered as a key factor but may aid in precision oncology by identifying different patient populations that are likely not going to respond to ICI. Furthermore, our results suggest that targeting PSME4 may be a novel approach for sensitizing the immune system. As a follow up to our study, we are now collaborating with Ben Cravatt, to test a molecule that may prohibit PSME4-mediated proteasomal activity and therefore may offer a novel therapeutic opportunity to cancer patients expressing high levels of PSME4.
The discovery of proteasomal-cleaved peptides as potential antimicrobial peptides will open a new chapter in innate immunity and our understanding of the role proteasomes may have played in cell-autonomous defense in evolution. This discovery could not have been made without the ability to detect proteasomal-cleaved peptides in their native form, in which the natural information of the peptide cleavage is retained, relying on the MAPP technology we developed during the starting ERC grant.