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Article ; Online: Multi-faceted role of LRP1 in the immune system.

Sizova, Olga / John, Lisa St / Ma, Qing / Molldrem, Jeffrey J

2023 Volume 14, Page(s) 1166189

Abstract: Graft versus host disease (GVHD) represents the major complication after allogeneic hematopoietic stem cell transplantation (Allo-SCT). GVHD-prone patients rely on GVHD prophylaxis (e.g. methotrexate) and generalized anti-GVHD medical regimen ( ... ...

Abstract	Graft versus host disease (GVHD) represents the major complication after allogeneic hematopoietic stem cell transplantation (Allo-SCT). GVHD-prone patients rely on GVHD prophylaxis (e.g. methotrexate) and generalized anti-GVHD medical regimen (glucocorticoids). New anti-GVHD therapy strategies are being constantly explored, however there is an urgent need to improve current treatment, since GVHD-related mortality reaches 22% within 5 years in patients with chronic GVHD. This review is an attempt to describe a very well-known receptor in lipoprotein studies - the low-density lipoprotein receptor related protein 1 (LRP1) - in a new light, as a potential therapeutic target for GVHD prevention and treatment. Our preliminary studies demonstrated that LRP1 deletion in donor murine T cells results in significantly lower GVHD-related mortality in recipient mice with MHC (major histocompatibility complex) -mismatched HSCT. Given the importance of T cells in the development of GVHD, there is a significant gap in scientific literature regarding LRP1's role in T cell biology. Furthermore, there is limited research interest and publications on this classical receptor molecule in other immune cell types. Herein, we endeavor to summarize existing knowledge about LRP1's role in various immune cells to demonstrate the possibility of this receptor to serve as a novel target for anti-GVHD treatment.
MeSH term(s)	Animals ; Mice ; Transplantation, Homologous/adverse effects ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation/adverse effects ; T-Lymphocytes ; Methotrexate ; Low Density Lipoprotein Receptor-Related Protein-1
Chemical Substances	Methotrexate (YL5FZ2Y5U1) ; Lrp1 protein, mouse ; Low Density Lipoprotein Receptor-Related Protein-1
Language	English
Publishing date	2023-03-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1166189
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Article ; Online: What T cells see in WT-1.

Molldrem, Jeffrey J

Blood

2012 Volume 120, Issue 8, Page(s) 1540–1541

Abstract: The Wilms tumor protein, WT-1, is a widely recognized tumor antigen that is aberrantly expressed in myeloid and lymphoid leukemia and in this issue of Blood, Doubrovina et al report the most extensive catalog heretofore of HLA-restricted immunogenic ... ...

Abstract	The Wilms tumor protein, WT-1, is a widely recognized tumor antigen that is aberrantly expressed in myeloid and lymphoid leukemia and in this issue of Blood, Doubrovina et al report the most extensive catalog heretofore of HLA-restricted immunogenic peptides derived from WT-1, which are recognized by CD8 and CD4T cells.
MeSH term(s)	Epitopes, T-Lymphocyte/immunology ; HLA Antigens/immunology ; Humans ; Leukemia/immunology ; Peptides/immunology ; T-Lymphocytes/immunology ; WT1 Proteins/immunology
Chemical Substances	Epitopes, T-Lymphocyte ; HLA Antigens ; Peptides ; WT1 Proteins
Language	English
Publishing date	2012-08-20
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2012-06-433979
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Zs.MO 364: Show issues

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Article ; Online: Identification of Nonfunctional Alternatively Spliced Isoforms of STING in Human Acute Myeloid Leukemia.

Boda, Akash R / Liu, Arthur J / Castro-Pando, Susana / Whitfield, Benjamin T / Molldrem, Jeffrey J / Al-Atrash, Gheath / Di Francesco, Maria Emilia / Jones, Philip / Ager, Casey R / Curran, Michael A

Cancer research communications

2024 Volume 4, Issue 3, Page(s) 911–918

Abstract: Lack of robust activation of Stimulator of Interferon Genes (STING) pathway and subsequent induction of type I IFN responses is considered a barrier to antitumor immunity in acute myeloid leukemia (AML). Using common human AML cell lines as in vitro ... ...

Abstract	Lack of robust activation of Stimulator of Interferon Genes (STING) pathway and subsequent induction of type I IFN responses is considered a barrier to antitumor immunity in acute myeloid leukemia (AML). Using common human AML cell lines as in vitro tools to evaluate the efficacy of novel STING agonists, we found most AML lines to be poor producers of IFNs upon exposure to extremely potent agonists, suggesting cell-intrinsic suppression of STING signaling may occur. We observed unexpected patterns of response that did not correlate with levels of STING pathway components or of known enzymes associated with resistance. To identify a genetic basis for these observations, we cloned and sequenced STING from the cDNA of human AML cell lines and found both frequent mutations and deviations from normal RNA splicing. We identified two novel spliced isoforms of STING in these lines and validated their expression in primary human AML samples. When transduced into reporter cells, these novel STING isoforms exhibited complete insensitivity to agonist stimulation. These observations identify alternative splicing as a mechanism of STING pathway suppression and suggest that most AML silences the STING pathway through direct modification rather than through engagement of external inhibitory factors. Significance: We find that AML acquires resistance to innate immune activation via the STING pathway through aberrant splicing of the STING transcript including two novel forms described herein that act as dominant negatives. These data broaden understanding of how cancers evolve STING resistance, and suggest that the AML tumor microenvironment, not the cancer cell, should be the target of therapeutic interventions to activate STING.
MeSH term(s)	Humans ; Protein Isoforms/genetics ; Leukemia, Myeloid, Acute/genetics ; Alternative Splicing/genetics ; Interferon Type I/genetics ; Cell Line ; Tumor Microenvironment
Chemical Substances	Protein Isoforms ; Interferon Type I
Language	English
Publishing date	2024-03-13
Publishing country	United States
Document type	Journal Article
ISSN	2767-9764
ISSN (online)	2767-9764
DOI	10.1158/2767-9764.CRC-24-0095
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Article ; Online: Preparing basic and translational grant proposals: thoughts from the trenches.

Molldrem, Jeffrey J

Hematology. American Society of Hematology. Education Program

2010 Volume 2010, Page(s) 181–184

Abstract: Written primarily for first-time applicants, this overview is a collection of tips intended to convey an approach to grant writing based on the experience of the author. Therefore, it is not a comprehensive review and it does not supplant the numerous ... ...

Abstract	Written primarily for first-time applicants, this overview is a collection of tips intended to convey an approach to grant writing based on the experience of the author. Therefore, it is not a comprehensive review and it does not supplant the numerous treatises on grant writing, which cover everything from writing style and grammar to details regarding individual granting mechanisms and agencies. Rather, it is a brief overview of the grant writing process from conception to submission.
MeSH term(s)	Academies and Institutes ; Budgets ; Financing, Organized ; Research Support as Topic ; Translational Medical Research
Language	English
Publishing date	2010
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1520-4383
ISSN (online)	1520-4383
DOI	10.1182/asheducation-2010.1.181
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Article ; Online: A GVHD kill switch helps immune reconstitution.

Molldrem, Jeffrey J / Lu, Sijie

Blood

2014 Volume 123, Issue 25, Page(s) 3849–3850

Abstract: In this issue of Blood, Zhou et al report long-term follow-up and detailed analysis of immune reconstitution associated with a different suicide gene strategy to abrogate graft-versus-host disease (GVHD). ...

Abstract	In this issue of Blood, Zhou et al report long-term follow-up and detailed analysis of immune reconstitution associated with a different suicide gene strategy to abrogate graft-versus-host disease (GVHD).
MeSH term(s)	Caspase 9/genetics ; Female ; Hematopoietic Stem Cell Transplantation/methods ; Humans ; Male ; T-Lymphocytes/transplantation ; Transgenes/genetics
Chemical Substances	Caspase 9 (EC 3.4.22.-)
Language	English
Publishing date	2014-06-17
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2014-05-572883
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Uh III Zs.140: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 364: Show issues

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Article ; Online: Targeting PR1 in myeloid leukemia.

Alatrash, Gheath / Molldrem, Jeffrey J / Qazilbash, Muzaffar H

Oncotarget

2017 Volume 9, Issue 4, Page(s) 4280–4281

Language	English
Publishing date	2017-12-18
Publishing country	United States
Document type	Editorial
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.23403
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Article: Vaccination for leukemia.

Molldrem, Jeffrey J

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

2006 Volume 12, Issue 1 Suppl 1, Page(s) 13–18

Abstract: Myeloid forms of leukemia would seem to be an ideal disease for investigators wishing to develop targeted immunotherapy because the leukemia is derived from antigen-presenting cells and because clinical data have demonstrated that there is potent T-cell ... ...

Abstract	Myeloid forms of leukemia would seem to be an ideal disease for investigators wishing to develop targeted immunotherapy because the leukemia is derived from antigen-presenting cells and because clinical data have demonstrated that there is potent T-cell immunity to chronic myeloid leukemia when donor lymphocyte infusions are used to treat relapse after transplantation. However, clinical vaccine studies have had to wait for the identification of specific antigens, some of which have recently been identified, and for a more complete understanding of basic tumor immunology. Here we review relevant fundamental T-cell biology, the nature of some important leukemia-associated antigens, and the preliminary results from recent clinical vaccine trials for leukemia. Although these studies are still early, they offer evidence that effective immunity to leukemia is possible after vaccination, thus setting the stage for future combined therapies.
MeSH term(s)	Animals ; Antigen-Presenting Cells/immunology ; Antigen-Presenting Cells/pathology ; Antigens, Neoplasm/immunology ; Antigens, Neoplasm/therapeutic use ; Cancer Vaccines/immunology ; Cancer Vaccines/therapeutic use ; Clinical Trials as Topic ; Combined Modality Therapy ; Humans ; Immunity, Cellular ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy ; T-Lymphocytes/immunology ; T-Lymphocytes/pathology ; Vaccination
Chemical Substances	Antigens, Neoplasm ; Cancer Vaccines
Language	English
Publishing date	2006-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1474865-4
ISSN	1083-8791
ISSN	1083-8791
DOI	10.1016/j.bbmt.2005.10.014
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Zs.A 5082: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 462: Show issues

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Article ; Online: Tsyn-Seq: a T-cell Synapse-Based Antigen Identification Platform.

Cancer immunology research

2024 Volume 12, Issue 5, Page(s) 530–543

Abstract: Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes ... ...

Abstract	Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell-APC aggregates were detected by dual-reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 antigen derived from human papillomavirus type 16 (HPV16), Tsyn-seq successfully enriched the correct cognate antigen from a cDNA library derived from an HPV16-positive cervical cancer cell line. Tsyn-seq provides a method for rapidly identifying antigens recognized by TCRs of interest from a tumor cDNA library. See related Spotlight by Makani and Joglekar, p. 515.
MeSH term(s)	Humans ; Receptors, Antigen, T-Cell/immunology ; Receptors, Antigen, T-Cell/genetics ; T-Lymphocytes/immunology ; High-Throughput Nucleotide Sequencing ; Papillomavirus E7 Proteins/immunology ; Papillomavirus E7 Proteins/genetics ; Gene Library ; Antigen-Presenting Cells/immunology ; NFATC Transcription Factors/metabolism ; NFATC Transcription Factors/immunology ; Cell Line, Tumor ; NF-kappa B/metabolism ; Immunological Synapses/immunology ; Human papillomavirus 16/immunology ; Human papillomavirus 16/genetics ; Female
Chemical Substances	Receptors, Antigen, T-Cell ; Papillomavirus E7 Proteins ; NFATC Transcription Factors ; oncogene protein E7, Human papillomavirus type 16 ; NF-kappa B
Language	English
Publishing date	2024-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-23-0467
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Article: Vaccinating transplant recipients.

Molldrem, Jeffrey J

Nature medicine

2005 Volume 11, Issue 11, Page(s) 1162–1163

MeSH term(s)	Hematopoietic Stem Cell Transplantation ; Humans ; Immunity, Innate ; Immunotherapy ; Pneumococcal Vaccines/therapeutic use ; T-Lymphocytes/immunology ; Transplantation, Homologous ; Treatment Outcome ; Vaccination
Chemical Substances	Pneumococcal Vaccines
Language	English
Publishing date	2005-11
Publishing country	United States
Document type	Comment ; Comparative Study ; News
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/nm1105-1162
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Zs.A 4212: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Immunologic Predictors for Clinical Responses during Immune Checkpoint Blockade in Patients with Myelodysplastic Syndromes.

Lee, Sung-Eun / Wang, Feng / Grefe, Maison / Trujillo-Ocampo, Abel / Ruiz-Vasquez, Wilfredo / Takahashi, Koichi / Abbas, Hussein A / Borges, Pamella / Antunes, Dinler Amaral / Al-Atrash, Gheath / Daver, Naval / Molldrem, Jeffrey J / Futreal, Andrew / Garcia-Manero, Guillermo / Im, Jin S

Clinical cancer research : an official journal of the American Association for Cancer Research

2023 Volume 29, Issue 10, Page(s) 1938–1951

Abstract: Purpose: The aim of this study is to determine immune-related biomarkers to predict effective antitumor immunity in myelodysplastic syndrome (MDS) during immunotherapy (IMT, αCTLA-4, and/or αPD-1 antibodies) and/or hypomethylating agent (HMA).: ... ...

Abstract	Purpose: The aim of this study is to determine immune-related biomarkers to predict effective antitumor immunity in myelodysplastic syndrome (MDS) during immunotherapy (IMT, αCTLA-4, and/or αPD-1 antibodies) and/or hypomethylating agent (HMA). Experimental design: Peripheral blood samples from 55 patients with MDS were assessed for immune subsets, T-cell receptor (TCR) repertoire, mutations in 295 acute myeloid leukemia (AML)/MDS-related genes, and immune-related gene expression profiling before and after the first treatment. Results: Clinical responders treated with IMT ± HMA but not HMA alone showed a significant expansion of central memory (CM) CD8+ T cells, diverse TCRβ repertoire pretreatment with increased clonality and emergence of novel clones after the initial treatment, and a higher mutation burden pretreatment with subsequent reduction posttreatment. Autophagy, TGFβ, and Th1 differentiation pathways were the most downregulated in nonresponders after treatment, while upregulated in responders. Finally, CTLA-4 but not PD-1 blockade attributed to favorable changes in immune landscape. Conclusions: Analysis of tumor-immune landscape in MDS during immunotherapy provides clinical response biomarkers.
MeSH term(s)	Humans ; Immune Checkpoint Inhibitors/therapeutic use ; Myelodysplastic Syndromes/drug therapy ; Myelodysplastic Syndromes/genetics ; Myelodysplastic Syndromes/pathology ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Immunotherapy
Chemical Substances	Immune Checkpoint Inhibitors
Language	English
Publishing date	2023-03-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-22-2601
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