Expanded tumor-associated polymorphonuclear myeloid-derived suppressor cells in Waldenstrom macroglobulinemia display immune suppressive activity
Abstract The role of the bone marrow (BM) microenvironment in regulating the antitumor immune response in Waldenstrom macroglobulinemia (WM) remains poorly understood. Here we transcriptionally and phenotypically profiled non-malignant (CD19- CD138-) BM cells from WM patients with a focus on myeloid...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-12-01
|
| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-024-01173-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850134468008869888 |
|---|---|
| author | Vaishali Bhardwaj Zhi-Zhang Yang Shahrzad Jalali Jose C. Villasboas Rekha Mudappathi Junwen Wang Prithviraj Mukherjee Jonas Paludo Xinyi Tang Hyo Jin Kim Jordan E. Krull Kerstin Wenzl Anne J. Novak Patrizia Mondello Stephen M. Ansell |
| author_facet | Vaishali Bhardwaj Zhi-Zhang Yang Shahrzad Jalali Jose C. Villasboas Rekha Mudappathi Junwen Wang Prithviraj Mukherjee Jonas Paludo Xinyi Tang Hyo Jin Kim Jordan E. Krull Kerstin Wenzl Anne J. Novak Patrizia Mondello Stephen M. Ansell |
| author_sort | Vaishali Bhardwaj |
| collection | DOAJ |
| description | Abstract The role of the bone marrow (BM) microenvironment in regulating the antitumor immune response in Waldenstrom macroglobulinemia (WM) remains poorly understood. Here we transcriptionally and phenotypically profiled non-malignant (CD19- CD138-) BM cells from WM patients with a focus on myeloid derived suppressive cells (MDSCs) to provide a deeper understanding of their role in WM. We found that HLA-DRlowCD11b+CD33+ MDSCs were significantly increased in WM patients as compared to normal controls, with an expansion of predominantly polymorphonuclear (PMN)-MDSCs. Single-cell immunogenomic profiling of WM MDSCs identified an immune-suppressive gene signature with upregulated inflammatory pathways associated with interferon and tumor necrosis factor (TNF) signaling. Gene signatures associated with an inflammatory and immune suppressive environment were predominately expressed in PMN-MDSCs. In vitro, WM PMN-MDSCs demonstrated robust T-cell suppression and their viability and expansion was notably enhanced by granulocyte colony stimulating factor (G-CSF) and TNFα. Furthermore, BM malignant B-cells attracted PMN-MDSCs to a greater degree than monocytic MDSCs. Collectively, these data suggest that malignant WM B cells actively recruit PMN-MDSCs which promote an immunosuppressive BM microenvironment through a direct T cell inhibition, while release of G-CSF/TNFα in the microenvironment further promotes PMN-MDSC expansion and in turn immune suppression. Targeting PMN-MDSCs may therefore represent a potential therapeutic strategy in patients with WM. |
| format | Article |
| id | doaj-art-73a4e0ff95a04bec9708ae3f76ab728c |
| institution | OA Journals |
| issn | 2044-5385 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Blood Cancer Journal |
| spelling | doaj-art-73a4e0ff95a04bec9708ae3f76ab728c2025-08-20T02:31:41ZengNature Publishing GroupBlood Cancer Journal2044-53852024-12-0114111310.1038/s41408-024-01173-wExpanded tumor-associated polymorphonuclear myeloid-derived suppressor cells in Waldenstrom macroglobulinemia display immune suppressive activityVaishali Bhardwaj0Zhi-Zhang Yang1Shahrzad Jalali2Jose C. Villasboas3Rekha Mudappathi4Junwen Wang5Prithviraj Mukherjee6Jonas Paludo7Xinyi Tang8Hyo Jin Kim9Jordan E. Krull10Kerstin Wenzl11Anne J. Novak12Patrizia Mondello13Stephen M. Ansell14Division of Hematology and Internal Medicine Mayo ClinicDivision of Hematology and Internal Medicine Mayo ClinicDivision of Hematology and Internal Medicine Mayo ClinicDivision of Hematology and Internal Medicine Mayo ClinicDepartment of Quantitative Health Sciences and Center for Individualized Medicine, Mayo Clinic ArizonaDepartment of Quantitative Health Sciences and Center for Individualized Medicine, Mayo Clinic ArizonaDivision of Hematology and Internal Medicine Mayo ClinicDivision of Hematology and Internal Medicine Mayo ClinicDivision of Hematology and Internal Medicine Mayo ClinicDivision of Hematology and Internal Medicine Mayo ClinicDivision of Hematology and Internal Medicine Mayo ClinicDivision of Hematology and Internal Medicine Mayo ClinicDivision of Hematology and Internal Medicine Mayo ClinicDivision of Hematology and Internal Medicine Mayo ClinicDivision of Hematology and Internal Medicine Mayo ClinicAbstract The role of the bone marrow (BM) microenvironment in regulating the antitumor immune response in Waldenstrom macroglobulinemia (WM) remains poorly understood. Here we transcriptionally and phenotypically profiled non-malignant (CD19- CD138-) BM cells from WM patients with a focus on myeloid derived suppressive cells (MDSCs) to provide a deeper understanding of their role in WM. We found that HLA-DRlowCD11b+CD33+ MDSCs were significantly increased in WM patients as compared to normal controls, with an expansion of predominantly polymorphonuclear (PMN)-MDSCs. Single-cell immunogenomic profiling of WM MDSCs identified an immune-suppressive gene signature with upregulated inflammatory pathways associated with interferon and tumor necrosis factor (TNF) signaling. Gene signatures associated with an inflammatory and immune suppressive environment were predominately expressed in PMN-MDSCs. In vitro, WM PMN-MDSCs demonstrated robust T-cell suppression and their viability and expansion was notably enhanced by granulocyte colony stimulating factor (G-CSF) and TNFα. Furthermore, BM malignant B-cells attracted PMN-MDSCs to a greater degree than monocytic MDSCs. Collectively, these data suggest that malignant WM B cells actively recruit PMN-MDSCs which promote an immunosuppressive BM microenvironment through a direct T cell inhibition, while release of G-CSF/TNFα in the microenvironment further promotes PMN-MDSC expansion and in turn immune suppression. Targeting PMN-MDSCs may therefore represent a potential therapeutic strategy in patients with WM.https://doi.org/10.1038/s41408-024-01173-w |
| spellingShingle | Vaishali Bhardwaj Zhi-Zhang Yang Shahrzad Jalali Jose C. Villasboas Rekha Mudappathi Junwen Wang Prithviraj Mukherjee Jonas Paludo Xinyi Tang Hyo Jin Kim Jordan E. Krull Kerstin Wenzl Anne J. Novak Patrizia Mondello Stephen M. Ansell Expanded tumor-associated polymorphonuclear myeloid-derived suppressor cells in Waldenstrom macroglobulinemia display immune suppressive activity Blood Cancer Journal |
| title | Expanded tumor-associated polymorphonuclear myeloid-derived suppressor cells in Waldenstrom macroglobulinemia display immune suppressive activity |
| title_full | Expanded tumor-associated polymorphonuclear myeloid-derived suppressor cells in Waldenstrom macroglobulinemia display immune suppressive activity |
| title_fullStr | Expanded tumor-associated polymorphonuclear myeloid-derived suppressor cells in Waldenstrom macroglobulinemia display immune suppressive activity |
| title_full_unstemmed | Expanded tumor-associated polymorphonuclear myeloid-derived suppressor cells in Waldenstrom macroglobulinemia display immune suppressive activity |
| title_short | Expanded tumor-associated polymorphonuclear myeloid-derived suppressor cells in Waldenstrom macroglobulinemia display immune suppressive activity |
| title_sort | expanded tumor associated polymorphonuclear myeloid derived suppressor cells in waldenstrom macroglobulinemia display immune suppressive activity |
| url | https://doi.org/10.1038/s41408-024-01173-w |
| work_keys_str_mv | AT vaishalibhardwaj expandedtumorassociatedpolymorphonuclearmyeloidderivedsuppressorcellsinwaldenstrommacroglobulinemiadisplayimmunesuppressiveactivity AT zhizhangyang expandedtumorassociatedpolymorphonuclearmyeloidderivedsuppressorcellsinwaldenstrommacroglobulinemiadisplayimmunesuppressiveactivity AT shahrzadjalali expandedtumorassociatedpolymorphonuclearmyeloidderivedsuppressorcellsinwaldenstrommacroglobulinemiadisplayimmunesuppressiveactivity AT josecvillasboas expandedtumorassociatedpolymorphonuclearmyeloidderivedsuppressorcellsinwaldenstrommacroglobulinemiadisplayimmunesuppressiveactivity AT rekhamudappathi expandedtumorassociatedpolymorphonuclearmyeloidderivedsuppressorcellsinwaldenstrommacroglobulinemiadisplayimmunesuppressiveactivity AT junwenwang expandedtumorassociatedpolymorphonuclearmyeloidderivedsuppressorcellsinwaldenstrommacroglobulinemiadisplayimmunesuppressiveactivity AT prithvirajmukherjee expandedtumorassociatedpolymorphonuclearmyeloidderivedsuppressorcellsinwaldenstrommacroglobulinemiadisplayimmunesuppressiveactivity AT jonaspaludo expandedtumorassociatedpolymorphonuclearmyeloidderivedsuppressorcellsinwaldenstrommacroglobulinemiadisplayimmunesuppressiveactivity AT xinyitang expandedtumorassociatedpolymorphonuclearmyeloidderivedsuppressorcellsinwaldenstrommacroglobulinemiadisplayimmunesuppressiveactivity AT hyojinkim expandedtumorassociatedpolymorphonuclearmyeloidderivedsuppressorcellsinwaldenstrommacroglobulinemiadisplayimmunesuppressiveactivity AT jordanekrull expandedtumorassociatedpolymorphonuclearmyeloidderivedsuppressorcellsinwaldenstrommacroglobulinemiadisplayimmunesuppressiveactivity AT kerstinwenzl expandedtumorassociatedpolymorphonuclearmyeloidderivedsuppressorcellsinwaldenstrommacroglobulinemiadisplayimmunesuppressiveactivity AT annejnovak expandedtumorassociatedpolymorphonuclearmyeloidderivedsuppressorcellsinwaldenstrommacroglobulinemiadisplayimmunesuppressiveactivity AT patriziamondello expandedtumorassociatedpolymorphonuclearmyeloidderivedsuppressorcellsinwaldenstrommacroglobulinemiadisplayimmunesuppressiveactivity AT stephenmansell expandedtumorassociatedpolymorphonuclearmyeloidderivedsuppressorcellsinwaldenstrommacroglobulinemiadisplayimmunesuppressiveactivity |