Background
Immune checkpoint inhibition (ICI) therapy has revolutionized cancer treatment, but our understanding of the mechanisms underlying resistance remains limited. The cellular proteasome, which regulates antigen processing, antigen presentation, inflammatory signaling, and immune cell activation, is crucial in modulating anti-tumor immunity. However, the impact of proteasome complex heterogeneity on tumor development and response to immunotherapy has yet to be systematically investigated.
Merav et al. demonstrate significant variations in the composition of the proteasome complex among different cancers, which impact tumor-immune interactions and cellular responses to the environment.
By analyzing the degradation patterns of patient-derived non-small cell lung cancer samples, the study discovered an upregulation of the proteasome regulator PSME4 in tumors, altering proteasome activity, diminishing antigen diversity, and correlating with a lack of response to immunotherapy.
Experiment and Result
Heterogeneity of the Proteasome Complex
Researchers systematically examined the heterogeneity of the proteasome complex and its response to ICI in hundreds of patients with bladder cancer, lung cancer, melanoma, or kidney cancer. They found significant variations in the composition of the proteasome complex among different cancer types and individual patients.
Although the non-labeled quantitative mass spectrometry (LFQ-MS) analysis of cell lines indicated that less than 5% of 20S proteasomes carried the regulatory factor PSME4, the results suggested an increased frequency of PSME4 in many cancer types.
Given the association of PSME4 with histone organization, DNA damage sensing, and repair, and the known sensitivity of non-small cell lung cancer (NSCLC) to proteotoxic stress, researchers speculated that upregulation of PSME4 may provide a protective mechanism.
PSME4 in NSCLC
To investigate pathways that PSME4 levels may influence, researchers stratified tumors in the CPTAC-LUAD proteomic cohort (n = 110) based on the abundance of different regulatory subunits. Using multiple annotation sets, they found that T cell-related pathways were most enriched in tumors with low PSME4 expression.
Furthermore, the study revealed a significant reduction in the "T cell markers" defined by GZMA, GZMB, PRF1, CXCL9, CXCL10, CD8A, and CD4 in tumors enriched with PSME4. These findings suggest that the observed upregulation of PSME4 in NSCLC may be associated with T cell-mediated antitumor immunity.
As PSME4 is predominantly expressed in cancerous tissues, researchers also investigated whether it affects the transcriptional programs and tumor inflammation in NSCLC. Through biochemical assays, the study found that PSME4 interacts with constitutive proteasomes and immunoproteasomes in human lung cancer cell lines. Additionally, it was observed that PSME4 binds to immunoproteasomes and attenuates the activity of all immunoproteasome-associated proteins.
Animal Experiments
To assess the impact of PSME4 on tumor progression, researchers tracked tumor-bearing mice carrying KP1.9 PSME4 KD, parental KP1.9 and overexpressed KP1.9 PSME4 OE tumors to uncover the influence of PSME4 on tumor-immune interactions.
By evaluating lymphocyte infiltration in mice lung tumors seven weeks after tumor injection, the study found reduced tumor inflammation and decreased T cell activation in mice with KP1.9PSME4 OE tumors. These data suggest that increased levels of PSME4 in tumors promote an immune-suppressive tumor microenvironment.
Furthermore, it was observed that splenic lymphocytes from mice with KP1.9 PSME4 OE tumors exhibited reduced cytotoxicity against KP1.9 cells. Conversely, splenic lymphocytes from KP1.9 PSME4 KD tumor-bearing mice demonstrated more potent cytotoxicity. This indicates that antitumor activity indeed relies on the absence of PSME4 in KP1.9 tumor cells.
Conclusion
This study highlights the heterogeneity of proteasome regulatory function within patients as a crucial factor in controlling tumor immunogenicity and immune therapy response. The research demonstrates that alterations in proteasome composition and function contribute to the formation of tumor-host interactions. In NSCLC, it has been shown that PSME4 plays an anti-inflammatory role in cancer by reducing immune proteasome activity. The changes in proteasome activity, in turn, lead to a decrease in antigenicity.
Reference
[1] Javitt, A., Shmueli, M.D., Kramer, M.P. et al. The proteasome regulator PSME4 modulates proteasome activity and antigen diversity to abrogate antitumor immunity in NSCLC. Nat Cancer 4, 629–647 (2023). https://doi.org/10.1038/s43018-023-00557-4
