PD-1/PD-L1, MDSC Pathways, and Checkpoint Inhibitor Therapy in Ph(-) Myeloproliferative Neoplasm: A Review
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1Division of Hematology/Oncology, Brookdale University Hospital Medical Center, Brooklyn, NY 11212, USA.
Abstract:
There has been significant progress in immune checkpoint inhibitor (CPI) therapy in many solid tumor types. However, only a single failed study has been published in treating Ph(-) myeloproliferative neoplasm (MPN). To make progress in CPI studies on this disease, herein, we review and summarize the mechanisms of activation of the PD-L1 promoter, which are as follows: (a) the extrinsic mechanism, which is activated by interferon gamma (IFN γ) by tumor infiltration lymphocytes (TIL) and NK cells; (b) the intrinsic mechanism of EGFR or PTEN loss resulting in the activation of the MAPK and AKT pathways and then stat 1 and 3 activation; and (c) 9p24 amplicon amplification, resulting in PD-L1 and Jak2 activation. We also review the literature and postulate that many of the failures of CPI therapy in MPN are likely due to excessive MDSC activities. We list all of the anti-MDSC agents, especially those with ruxolitinib, IMID compounds, and BTK inhibitors, which may be combined with CPI therapy in the future as part of clinical trials applying CPI therapy to Ph(-) MPN.
Insights
Immune checkpoint inhibitors show promise in solid tumors but have failed in Philadelphia chromosome-negative myeloproliferative neoplasms (MPN). Excessive myeloid-derived suppressor cells (MDSCs) may explain these failures, suggesting combination therapies for future MPN clinical trials.
Area of Science:
- Oncology
- Immunology
- Hematology
Background:
- Immune checkpoint inhibitors (CPI) have advanced cancer treatment for solid tumors.
- Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) have shown limited success with CPI therapy.
Purpose of the Study:
- To review and summarize PD-L1 promoter activation mechanisms in MPN.
- To identify potential reasons for CPI therapy failure in MPN.
- To propose novel therapeutic strategies combining CPI with anti-MDSC agents.
Main Methods:
- Review of literature on PD-L1 promoter activation pathways (extrinsic, intrinsic, and amplicon-driven).
- Analysis of factors contributing to CPI resistance in MPN.
- Identification of anti-myeloid-derived suppressor cell (MDSC) agents for potential combination therapy.
Main Results:
- PD-L1 promoter activation involves extrinsic (IFN-γ), intrinsic (EGFR/PTEN loss), and amplicon (9p24) mechanisms.
- Excessive MDSC activity is postulated as a key factor limiting CPI efficacy in MPN.
- Several anti-MDSC agents, including ruxolitinib, IMID compounds, and BTK inhibitors, are identified.
Conclusions:
- Understanding PD-L1 regulation is crucial for advancing CPI therapy in MPN.
- Targeting MDSCs in combination with CPI may overcome treatment resistance in MPN.
- Future clinical trials should explore combined CPI and anti-MDSC strategies for Philadelphia chromosome-negative MPN.
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