Dissertation
Plasma cells in malignant peripheral nerve sheath tumor response to kinase inhibitor therapy and immune checkpoint blockade
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2025
DOI: 10.25820/etd.007918
Abstract
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are lethal, Ras-driven sarcomas that fail to respond to chemotherapy and radiation. Immune checkpoint blockade (ICB) therapy has provided sustained anti-tumor activity for other cancers but it has disappointingly not yielded promising results as a monotherapy for MPNSTs. The only curative option for patients is complete surgical resection, which is difficult due to the location of the tumor along the nerve. Recent advances in the field have outlined how precursor lesions, plexiform neurofibromas (PNFs), transform into MPNSTs, providing key insight into potentially relevant therapies for patients. Working with a team of investigators at the University of Iowa, we evaluated patientmatched PNFs and MPNSTs to identify drug targets to test preclinically. We found that downstream effectors of Ras, MEK and Cyclin Dependent Kinases 4 and 6 (CDK4/6), are hyperactivated in MPNSTs and represent actionable clinical targets for the management of these aggressive tumors.
In Chapter 2, we demonstrate that combined inhibition of CDK4/6 and MEK effectively combats MPNSTs. Single-agent inhibitors induced modest cell death and senescence in vitro, but the combination works synergistically, surpassing the effects of either drug alone. The combination proved useful in slowing the growth of most patient-derived xenografts (PDXs) tested in immunodeficient mice. Using an immune competent mouse model of de novo MPNSTs, we found that dual CDK4/6-MEK inhibition causes tumor regression by activating anti-tumor immunity. Regressing tumors had a unique phenotype of elevated plasma cells and CD8+ T cells whereas terminal, drug-resistant tumors adopted an immunosuppressive microenvironment characterized by abundant M2 macrophages and increased programmed-death ligand 1 (PD-L1) expression on tumor cells. I hypothesized that ICB therapy targeting PD-L1 would overcome resistance to CDK4/6-MEK inhibition. Indeed, adjuvant anti-PD-L1 therapy significantly extended tumor regression caused by dual CDK4/6-MEK inhibition and markedly improved survival with some mice achieving apparent cure. These data revealed that inhibitors of CDK4/6 and MEK kinases sensitize MPNSTs to anti-PD-L1 therapy. Such findings are exciting because they suggest that combined inhibition of those kinases remodels an immunologically “cold” microenvironment in MPNSTs to an immunologically “hot” milieu that boosts their response to ICB immunotherapy.
In Chapter 3, I explore the role of plasma cells in sarcoma patient survival and MPNST response to therapy. In other human cancers, intratumoral plasma cells correlate with better patient survival and improved response to ICB therapy. My analyses of The Cancer Genome Atlas Sarcoma (TCGA SARC) database concur and show elevated tumor plasma cells prognose increased survival for sarcoma patients. To test the importance of plasma cells in MPNST pathobiology, I compared de novo MPNST initiation, progression, and response to therapy in wild-type mice to AID-/-; µS-/- mice that selectively lack plasma cells. The absence of plasma cells had no effect on MPNST initiation, progression, or the ability of dual CDK4/6-MEK inhibition to cause early tumor regression and delayed outgrowth. By comparison, I discovered that intratumoral plasma cells are required for MPNST response to anti-PD-L1 therapy. MPNSTs lacking plasma cells were less responsive to anti-PD-L1 monotherapy and treatment with CDK4/6-MEK inhibitors no longer sensitized the tumors to anti-PD-L1 therapy. Single cell transcriptomics and RT-qPCR validation revealed that CDK4/6-MEK inhibition activates a proinflammatory CD8+ T cell response involving major histocompatibility class I (MHC-I) antigen presentation in wild-type tumors. In contrast, MPNSTs lacking plasma cells displayed a CD4+ T cell response with MHC-II molecules on antigen presenting cells. This study provides the first viii evidence in any tumor type for a critical role of plasma cells in remodeling the immune landscape within drug-treated tumors. Specifically, plasma cells orchestrate a CD8-positive, proinflammatory state following CDK4/6-MEK inhibition that is required for response to ICB therapy in MPNSTs.
In Chapter 4, I briefly summarize my findings and consider future directions stimulated by this work. First, I highlight the potential value of activating the complement cascade as a functional biomarker of sensitivity to ICB therapy. Second, I propose a role for transforming growth factor beta (TGFb) in the MPNST response to dual CDK4/6-MEK inhibition and subsequent acquisition of drug resistance. Finally, I end by discussing unique mechanisms by which plasma cells may control T cell activity through hepatocyte growth factor (HGF)/MET signaling.
In the Appendix, I discuss how RABL6A (Rab-like GTPase isoform 6A), a newly discovered driver of MPNST progression that was originally identified by our lab may promote the expression of PD-L1 in MPNSTs.
Collectively, this thesis describes new insights into MPNST immune biology and novel mechanisms by which clinicians may predict and promote MPNST sensitivity to ICB immunotherapy. The unique role for plasma cells in controlling anti-tumor immunity identified herein is expected to have broad relevance for the effective treatment of other solid cancers with immune-based therapies.
Details
- Title: Subtitle
- Plasma cells in malignant peripheral nerve sheath tumor response to kinase inhibitor therapy and immune checkpoint blockade
- Creators
- Joshua James Lingo
- Contributors
- Dawn Quelle (Advisor)Benjamin Darbro (Committee Member)Rebecca Dodd (Committee Member)David Gordon (Committee Member)Gail Bishop (Committee Member)David Meyerholz (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Cancer Biology)
- Date degree season
- Spring 2025
- DOI
- 10.25820/etd.007918
- Publisher
- University of Iowa
- Number of pages
- xvi, 164 pages
- Copyright
- Copyright 2025 Joshua Lingo
- Language
- English
- Date submitted
- 04/27/2025
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 127-149).
- Public Abstract (ETD)
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are deadly cancers that arise along the nerve in the trunk and extremities. MPNSTs fail to respond to chemotherapy and the only curative option for patients is complete surgical resection. This highlights the need for more effective therapies in MPNST that leverage key features of MPNST biology and the immune system. MPNSTs are considered immunologically “cold” tumors, meaning they have low infiltrating anti-tumor immune cells. While immunotherapy has been revolutionary in providing sustained anti-tumor immunity for some cancers, it has so far not worked well for treating MPNSTs.
By defining key differences between patient MPNSTs and their benign precursor lesions, we identified two oncogenic kinases (CDK4/6 and MEK) that could be targeted together to effectively delay MPNST growth. Combining the inhibitors reduced the proliferation of MPNST cells far better than either drug alone. Excitingly, combined kinase inhibition in a mouse model of MPNST caused dramatic tumor shrinkage and activation of anti-tumor immunity, which sensitized tumors to immunotherapy. I found that drug-sensitive tumors contained activated immune cells, namely tumor killing CD8+ T cells and antibody-producing plasma cells. Recently, plasma cells have been associated with better patient survival and response to immunotherapy in other cancers. I directly tested the importance of plasma cells in anticancer therapy and found that tumors lacking plasma cells fail to activate CD8+ T cells and are unable to respond to immunotherapy. This is the first research to show that plasma cells control the tumor response to immunotherapies by activating anti-tumor immunity.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984830922502771
Metrics
3 Record Views