SUMMARY:
UCLA researchers in the Department of Medicine have discovered an enzyme that downregulates tumor expression levels of PD-L1/L2 in MAPKi-resistant melanoma with the potential to enhance cancer immune surveillance and therapeutic efficacy in drug-resistant melanoma. TITLE: Methods to enhance cancer immune surveillance and therapeutic efficacy in melanoma by control of cancer cell-surface PD-L1/L2.
BACKGROUND:
Melanoma is one of the most common cancer types globally and the deadliest type of skin cancer. According to the American Cancer Society, nearly 100,000 new patients will be diagnosed with melanoma and 7,650 of these cases are expected to be fatal in 2022. Currently, two therapies have been developed to treat melanoma. One inhibits mitogen-activated protein kinases (MAPKs) pathway, while the other regulates expression and activity of programmed cell death protein 1 (PD-1) and its ligands, PD-L1 and L2. While MAPK inhibition (MAPKi) and anti-PD-1/L1 therapies effect antitumor responses by disparate mechanisms, around 50% of patients receiving either of these therapies develop resistance within the first year of therapy. As a result, researchers are exploring the rationally sequenced combination of these two therapies to help reduce resistance to either therapy. In response to both therapies, cancer cells can express high levels of PD-L1 and PD-L2 during quasi-mesenchymal transition, which enables cancer cells to metastasize and acquire resistance to treatments. Over the last decade, strategies to enhance cancer immune surveillance by reducing PD-L1 protein levels with post-translational modifications have been developed. However, no such strategy has been tested successfully in the clinic. INNOVATION: Researchers led by Dr. Roger Lo in the Department of Medicine have discovered an enzyme that regulates levels of PD-L1/L2 in tumor cells to prevent acquired resistance. Since targeted therapies, including MAPK inhibition in melanoma, leads to PD-L1/2 upregulation, UCLA researchers used mass spectrometry of immunoprecipitates from cells expressing PD-L2 to identify proteins that may regulate PD-L2 levels. They identified a ligase that binds to PD-L1/L2 and validated its mechanism and binding affinity to PD-L1/L2. To test its efficacy as a target for therapy, they conducted knockdowns and over-expression of the ligase in melanoma murine models that had undergone MAPK inhibitor therapy, and respectively saw acceleration and suppression of MAPK inhibitor resistance. Murine models with deficiency in the ligase showed less CD8+ T cell infiltration. Taken together, the researchers present a novel target for preventing development of resistance in melanoma.
POTENTIAL APPLICATIONS:
• Alleviate the immune evasion in immune checkpoint blockade therapy, including MAPK inhibitor therapy, PD-L1/2 targeted therapy, and combination therapies
• Enhance cancer immune surveillance
ADVANTAGES:
• Novel target for drug development
• Has broader implications for cancer as MAPK- and PD-1/L1-targeted therapies have shown clinical success in other cancer types
DEVELOPMENT-TO-DATE:
The UCLA researchers validated the relationship between expression of the identified enzyme to cancer cell survival rate in 471 melanoma patients. They have demonstrated knockdown and over-expression of the identified ligase accelerates and suppresses, respectively, resistance development to MAPK inhibitor therapy in murine models. This work was publicly disclosed in Cancer Discovery August 2022.
Related Papers (from the inventors only):
1. Yang, Z., Wang, Y., Liu, S., Deng, W., Lomeli, S. H., Moriceau, G., ... & Lo, R. S. (2022). Enhancing PD-L1 Degradation by ITCH during MAPK Inhibitor Therapy Suppresses Acquired Resistance. Cancer discovery, candisc-1463.
2. Hugo W, Shi H, Sun L, Piva M, Song C, Kong X, Moriceau G, Hong A, Dahlman KB, Johnson DB, Sosman JA, Ribas A, Lo RS. Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance. Cell 2015;162:1271-85
3. Hugo W, Zaretsky JM, Sun L, Song C, Homet-Moreno B, Hu-Lieskovan S, Berent-Maoz B, Pang J, Chmielowski B, Cherry G, Seja E, Lomeli S, Kong X, Kelley MC, Sosman JA, Johnson DB, Ribas A, Lo RS. Genomic and Transcriptomic Features of Resistance and Sensitivity to Anti-PD-1 Therapy in Metastatic Melanoma. Cell 2016;165:35-44
4. Hong A, Moriceau G, Sun L, Lomeli S, Piva M, Damoiseaux R, Holmen SL, Sharpless NE, Hugo W, Lo RS. Exploiting Drug Addiction Mechanisms to Select against MAPKi-Resistant Melanoma. Cancer Discov 2018;8:74-93
5. Hong A, Piva M, Liu S, Hugo W, Lomeli SH, Zoete V, Randolph CE, Yang Z, Wang Y, Lee JJ, Lo SJ, Sun L, Vega-Crespo A, Garcia AJ, Shackelford DB, Dubinett SM, Scumpia PO, Byrum SD, Tackett AJ, Donahue TR, Michielin O, Holmen SL, Ribas A, Moriceau G, Lo RS. Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Antitumor T-cell Immunity. Cancer Discov 2021;11:714-35
6. Wang Y, Liu S, Yang Z, Algazi AP, Lomeli SH, Wang Y, Othus M, Hong A, Wang X, Randolph CE, Jones AM, Bosenberg MW, Byrum SD, Tackett AJ, Lopez H, Yates C, Solit DB, Ribas A, Piva M, Moriceau G, Lo RS. Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy. Cancer Cell 2021
7. Song C, Piva M, Sun L, Hong A, Moriceau G, Kong X, Zhang H, Lomeli S, Qian J, Yu CC, Damoiseaux R, Kelley MC, Dahlman KB, Scumpia PO, Sosman JA, Johnson DB, Ribas A, Hugo W, Lo RS. Recurrent Tumor Cell-Intrinsic and -Extrinsic Alterations during MAPKi-Induced Melanoma Regression and Early Adaptation. Cancer Discov 2017;7:1248-65