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Article ; Online: Immunogenicity in renal cell carcinoma: shifting focus to alternative sources of tumour-specific antigens.

Wolf, Melissa M / Rathmell, W Kimryn / de Cubas, Aguirre A

2023 Volume 19, Issue 7, Page(s) 440–450

Abstract: Renal cell carcinoma (RCC) comprises a group of malignancies arising from the kidney with unique tumour-specific antigen (TSA) signatures that can trigger cytotoxic immunity. Two classes of TSAs are now considered potential drivers of immunogenicity in ... ...

Abstract	Renal cell carcinoma (RCC) comprises a group of malignancies arising from the kidney with unique tumour-specific antigen (TSA) signatures that can trigger cytotoxic immunity. Two classes of TSAs are now considered potential drivers of immunogenicity in RCC: small-scale insertions and deletions (INDELs) that result in coding frameshift mutations, and activation of human endogenous retroviruses. The presence of neoantigen-specific T cells is a hallmark of solid tumours with a high mutagenic burden, which typically have abundant TSAs owing to non-synonymous single nucleotide variations within the genome. However, RCC exhibits high cytotoxic T cell reactivity despite only having an intermediate non-synonymous single nucleotide variation mutational burden. Instead, RCC tumours have a high pan-cancer proportion of INDEL frameshift mutations, and coding frameshift INDELs are associated with high immunogenicity. Moreover, cytotoxic T cells in RCC subtypes seem to recognize tumour-specific endogenous retrovirus epitopes, whose presence is associated with clinical responses to immune checkpoint blockade therapy. Here, we review the distinct molecular landscapes in RCC that promote immunogenic responses, discuss clinical opportunities for discovery of biomarkers that can inform therapeutic immune checkpoint blockade strategies, and identify gaps in knowledge for future investigations.
MeSH term(s)	Humans ; Carcinoma, Renal Cell/pathology ; Antigens, Neoplasm/genetics ; Immune Checkpoint Inhibitors ; Kidney Neoplasms/pathology ; Nucleotides
Chemical Substances	Antigens, Neoplasm ; Immune Checkpoint Inhibitors ; Nucleotides
Language	English
Publishing date	2023-03-27
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2490366-8
ISSN	1759-507X ; 1759-5061
ISSN (online)	1759-507X
ISSN	1759-5061
DOI	10.1038/s41581-023-00700-5
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Article ; Online: Modeling clear cell renal cell carcinoma and therapeutic implications.

Wolf, Melissa M / Kimryn Rathmell, W / Beckermann, Kathryn E

Oncogene

2020 Volume 39, Issue 17, Page(s) 3413–3426

Abstract: Renal cell carcinoma (RCC) comprises a diverse group of malignancies arising from the nephron. The most prevalent type, clear cell renal cell carcinoma (ccRCC), is characterized by genetic mutations in factors governing the hypoxia signaling pathway, ... ...

Abstract	Renal cell carcinoma (RCC) comprises a diverse group of malignancies arising from the nephron. The most prevalent type, clear cell renal cell carcinoma (ccRCC), is characterized by genetic mutations in factors governing the hypoxia signaling pathway, resulting in metabolic dysregulation, heightened angiogenesis, intratumoral heterogeneity, and deleterious tumor microenvironmental (TME) crosstalk. Identification of specific genetic variances has led to therapeutic innovation and improved survival for patients with ccRCC. Current barriers to effective long-term therapeutic success highlight the need for continued drug development using improved modeling systems. ccRCC preclinical models can be grouped into three broad categories: cell line, mouse, and 3D models. Yet, the breadth of important unanswered questions in ccRCC research far exceeds the accessibility of model systems capable of carrying them out. Accordingly, we review the strengths, weaknesses, and therapeutic implications of each model system that are relied upon today.
MeSH term(s)	Animals ; Carcinoma, Renal Cell/genetics ; Carcinoma, Renal Cell/metabolism ; Carcinoma, Renal Cell/pathology ; Carcinoma, Renal Cell/therapy ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Kidney Neoplasms/genetics ; Kidney Neoplasms/metabolism ; Kidney Neoplasms/pathology ; Kidney Neoplasms/therapy ; Models, Biological ; Neovascularization, Pathologic/genetics ; Neovascularization, Pathologic/metabolism ; Neovascularization, Pathologic/pathology ; Neovascularization, Pathologic/therapy ; Tumor Microenvironment
Language	English
Publishing date	2020-03-02
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-020-1234-3
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Article: Tissue-Specific Dependence of Th1 Cells on the Amino Acid Transporter SLC38A1 in Inflammation.

Sugiura, Ayaka / Beier, Katherine L / Chi, Channing / Heintzman, Darren R / Ye, Xiang / Wolf, Melissa M / Patterson, Andrew R / Cephus, Jacqueline-Yvonne / Hong, Hanna S / Lyssiotis, Costas A / Newcomb, Dawn C / Rathmell, Jeffrey C

bioRxiv : the preprint server for biology

2023

Abstract: Amino acid (AA) uptake is essential for T cell metabolism and function, but how tissue sites and inflammation affect ... ...

Abstract	Amino acid (AA) uptake is essential for T cell metabolism and function, but how tissue sites and inflammation affect CD4
Language	English
Publishing date	2023-09-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.13.557496
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Article ; Online: VHL loss reprograms the immune landscape to promote an inflammatory myeloid microenvironment in renal tumorigenesis.

The Journal of clinical investigation

2024 Volume 134, Issue 8

Abstract: Clear cell renal cell carcinoma (ccRCC) is characterized by dysregulated hypoxia signaling and a tumor microenvironment (TME) highly enriched in myeloid and lymphoid cells. Loss of the von Hippel Lindau (VHL) gene is a critical early event in ccRCC ... ...

Abstract	Clear cell renal cell carcinoma (ccRCC) is characterized by dysregulated hypoxia signaling and a tumor microenvironment (TME) highly enriched in myeloid and lymphoid cells. Loss of the von Hippel Lindau (VHL) gene is a critical early event in ccRCC pathogenesis and promotes stabilization of HIF. Whether VHL loss in cancer cells affects immune cells in the TME remains unclear. Using Vhl WT and Vhl-KO in vivo murine kidney cancer Renca models, we found that Vhl-KO tumors were more infiltrated by immune cells. Tumor-associated macrophages (TAMs) from Vhl-deficient tumors demonstrated enhanced in vivo glucose consumption, phagocytosis, and inflammatory transcriptional signatures, whereas lymphocytes from Vhl-KO tumors showed reduced activation and a lower response to anti-programmed cell death 1 (anti-PD-1) therapy in vivo. The chemokine CX3CL1 was highly expressed in human ccRCC tumors and was associated with Vhl deficiency. Deletion of Cx3cl1 in cancer cells decreased myeloid cell infiltration associated with Vhl loss to provide a mechanism by which Vhl loss may have contributed to the altered immune landscape. Here, we identify cancer cell-specific genetic features that drove environmental reprogramming and shaped the tumor immune landscape, with therapeutic implications for the treatment of ccRCC.
MeSH term(s)	Animals ; Humans ; Mice ; Carcinogenesis/genetics ; Carcinoma, Renal Cell/genetics ; Cell Transformation, Neoplastic ; Kidney ; Kidney Neoplasms/genetics ; Tumor Microenvironment ; Von Hippel-Lindau Tumor Suppressor Protein/genetics
Chemical Substances	VHL protein, human (EC 6.3.2.-) ; VHL protein, mouse (EC 6.3.2.-) ; Von Hippel-Lindau Tumor Suppressor Protein (EC 2.3.2.27)
Language	English
Publishing date	2024-04-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI173934
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Article ; Online: Differential Effects of Glutamine Inhibition Strategies on Antitumor CD8 T Cells.

Madden, Matthew Z / Ye, Xiang / Chi, Channing / Fisher, Emilie L / Wolf, Melissa M / Needle, Gabriel A / Bader, Jackie E / Patterson, Andrew R / Reinfeld, Bradley I / Landis, Madelyn D / Hathaway, Emma S / Muka, Jason E / O'Neil, Richard T / Karijolich, John / Philip, Mary / Rathmell, Jeffrey C

Journal of immunology (Baltimore, Md. : 1950)

2023 Volume 211, Issue 4, Page(s) 563–575

Abstract: Activated T cells undergo metabolic reprogramming to meet anabolic, differentiation, and functional demands. Glutamine supports many processes in activated T cells, and inhibition of glutamine metabolism alters T cell function in autoimmune disease and ... ...

Abstract	Activated T cells undergo metabolic reprogramming to meet anabolic, differentiation, and functional demands. Glutamine supports many processes in activated T cells, and inhibition of glutamine metabolism alters T cell function in autoimmune disease and cancer. Multiple glutamine-targeting molecules are under investigation, yet the precise mechanisms of glutamine-dependent CD8 T cell differentiation remain unclear. We show that distinct strategies of glutamine inhibition by glutaminase-specific inhibition with small molecule CB-839, pan-glutamine inhibition with 6-diazo-5-oxo-l-norleucine (DON), or by glutamine-depleted conditions (No Q) produce distinct metabolic differentiation trajectories in murine CD8 T cells. T cell activation with CB-839 treatment had a milder effect than did DON or No Q treatment. A key difference was that CB-839-treated cells compensated with increased glycolytic metabolism, whereas DON and No Q-treated cells increased oxidative metabolism. However, all glutamine treatment strategies elevated CD8 T cell dependence on glucose metabolism, and No Q treatment caused adaptation toward reduced glutamine dependence. DON treatment reduced histone modifications and numbers of persisting cells in adoptive transfer studies, but those T cells that remained could expand normally upon secondary Ag encounter. In contrast, No Q-treated cells persisted well yet demonstrated decreased secondary expansion. Consistent with reduced persistence, CD8 T cells activated in the presence of DON had reduced ability to control tumor growth and reduced tumor infiltration in adoptive cell therapy. Overall, each approach to inhibit glutamine metabolism confers distinct effects on CD8 T cells and highlights that targeting the same pathway in different ways can elicit opposing metabolic and functional outcomes.
MeSH term(s)	Animals ; Mice ; Diazooxonorleucine/pharmacology ; Glutamine/metabolism ; Neoplasms/therapy ; Neoplasms/metabolism ; CD8-Positive T-Lymphocytes/metabolism
Chemical Substances	CB-839 ; Diazooxonorleucine (03J0H273KZ) ; Glutamine (0RH81L854J)
Language	English
Publishing date	2023-06-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2200715
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Article ; Online: STING-activating nanoparticles normalize the vascular-immune interface to potentiate cancer immunotherapy.

Wang-Bishop, Lihong / Kimmel, Blaise R / Ngwa, Verra M / Madden, Matthew Z / Baljon, Jessalyn J / Florian, David C / Hanna, Ann / Pastora, Lucinda E / Sheehy, Taylor L / Kwiatkowski, Alexander J / Wehbe, Mohamed / Wen, Xiaona / Becker, Kyle W / Garland, Kyle M / Schulman, Jacob A / Shae, Daniel / Edwards, Deanna / Wolf, Melissa M / Delapp, Rossane /

Christov, Plamen P / Beckermann, Kathryn E / Balko, Justin M / Rathmell, W Kimryn / Rathmell, Jeffrey C / Chen, Jin / Wilson, John T

Science immunology

2023 Volume 8, Issue 83, Page(s) eadd1153

Abstract: The tumor-associated vasculature imposes major structural and biochemical barriers to the infiltration of effector T cells and effective tumor control. Correlations between stimulator of interferon genes (STING) pathway activation and spontaneous T cell ... ...

Abstract	The tumor-associated vasculature imposes major structural and biochemical barriers to the infiltration of effector T cells and effective tumor control. Correlations between stimulator of interferon genes (STING) pathway activation and spontaneous T cell infiltration in human cancers led us to evaluate the effect of STING-activating nanoparticles (STANs), which are a polymersome-based platform for the delivery of a cyclic dinucleotide STING agonist, on the tumor vasculature and attendant effects on T cell infiltration and antitumor function. In multiple mouse tumor models, intravenous administration of STANs promoted vascular normalization, evidenced by improved vascular integrity, reduced tumor hypoxia, and increased endothelial cell expression of T cell adhesion molecules. STAN-mediated vascular reprogramming enhanced the infiltration, proliferation, and function of antitumor T cells and potentiated the response to immune checkpoint inhibitors and adoptive T cell therapy. We present STANs as a multimodal platform that activates and normalizes the tumor microenvironment to enhance T cell infiltration and function and augments responses to immunotherapy.
MeSH term(s)	Mice ; Animals ; Humans ; Neoplasms ; Immunotherapy ; T-Lymphocytes ; Nanoparticles ; Disease Models, Animal ; Tumor Microenvironment
Language	English
Publishing date	2023-05-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.add1153
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Article ; Online: Cell-programmed nutrient partitioning in the tumour microenvironment.

Reinfeld, Bradley I / Madden, Matthew Z / Wolf, Melissa M / Chytil, Anna / Bader, Jackie E / Patterson, Andrew R / Sugiura, Ayaka / Cohen, Allison S / Ali, Ahmed / Do, Brian T / Muir, Alexander / Lewis, Caroline A / Hongo, Rachel A / Young, Kirsten L / Brown, Rachel E / Todd, Vera M / Huffstater, Tessa / Abraham, Abin / O'Neil, Richard T /

Wilson, Matthew H / Xin, Fuxue / Tantawy, M Noor / Merryman, W David / Johnson, Rachelle W / Williams, Christopher S / Mason, Emily F / Mason, Frank M / Beckermann, Katherine E / Vander Heiden, Matthew G / Manning, H Charles / Rathmell, Jeffrey C / Rathmell, W Kimryn

Nature

2021 Volume 593, Issue 7858, Page(s) 282–288

Abstract: Cancer cells characteristically consume glucose through Warburg ... ...

Abstract	Cancer cells characteristically consume glucose through Warburg metabolism
MeSH term(s)	Animals ; Carcinoma, Renal Cell/immunology ; Carcinoma, Renal Cell/metabolism ; Carcinoma, Renal Cell/pathology ; Cell Line, Tumor ; Female ; Glucose/metabolism ; Glutamine/metabolism ; Humans ; Lipid Metabolism ; Male ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice ; Myeloid Cells/immunology ; Myeloid Cells/metabolism ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/pathology ; Nutrients/metabolism ; Tumor Microenvironment/immunology
Chemical Substances	Glutamine (0RH81L854J) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2021-04-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-021-03442-1
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Article ; Online: MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function.

Sugiura, Ayaka / Andrejeva, Gabriela / Voss, Kelsey / Heintzman, Darren R / Xu, Xincheng / Madden, Matthew Z / Ye, Xiang / Beier, Katherine L / Chowdhury, Nowrin U / Wolf, Melissa M / Young, Arissa C / Greenwood, Dalton L / Sewell, Allison E / Shahi, Shailesh K / Freedman, Samantha N / Cameron, Alanna M / Foerch, Patrik / Bourne, Tim / Garcia-Canaveras, Juan C /

Karijolich, John / Newcomb, Dawn C / Mangalam, Ashutosh K / Rabinowitz, Joshua D / Rathmell, Jeffrey C

Immunity

2021 Volume 55, Issue 1, Page(s) 65–81.e9

Abstract: Antigenic stimulation promotes T cell metabolic reprogramming to meet increased biosynthetic, bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) regulates de novo ... ...

Abstract	Antigenic stimulation promotes T cell metabolic reprogramming to meet increased biosynthetic, bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) regulates de novo purine synthesis and signaling in activated T cells to promote proliferation and inflammatory cytokine production. In pathogenic T helper-17 (Th17) cells, MTHFD2 prevented aberrant upregulation of the transcription factor FoxP3 along with inappropriate gain of suppressive capacity. MTHFD2 deficiency also promoted regulatory T (Treg) cell differentiation. Mechanistically, MTHFD2 inhibition led to depletion of purine pools, accumulation of purine biosynthetic intermediates, and decreased nutrient sensor mTORC1 signaling. MTHFD2 was also critical to regulate DNA and histone methylation in Th17 cells. Importantly, MTHFD2 deficiency reduced disease severity in multiple in vivo inflammatory disease models. MTHFD2 is thus a metabolic checkpoint to integrate purine metabolism with pathogenic effector cell signaling and is a potential therapeutic target within 1C metabolism pathways.
MeSH term(s)	Animals ; Cell Differentiation ; Cytokines/metabolism ; DNA Methylation ; Disease Models, Animal ; Humans ; Inflammation/immunology ; Inflammation Mediators/metabolism ; Lymphocyte Activation ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Methylenetetrahydrofolate Dehydrogenase (NADP)/genetics ; Methylenetetrahydrofolate Dehydrogenase (NADP)/metabolism ; Mice ; Mice, Transgenic ; Mutation/genetics ; Purines/biosynthesis ; Signal Transduction ; T-Lymphocytes, Regulatory/immunology ; Th17 Cells/immunology
Chemical Substances	Cytokines ; Inflammation Mediators ; Purines ; Methylenetetrahydrofolate Dehydrogenase (NADP) (EC 1.5.1.5) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
Language	English
Publishing date	2021-11-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2021.10.011
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Article: Mutant KRAS Exosomes Alter the Metabolic State of Recipient Colonic Epithelial Cells.

Zhang, Qin / Jeppesen, Dennis K / Higginbotham, James N / Demory Beckler, Michelle / Poulin, Emily J / Walsh, Alex J / Skala, Melissa C / McKinley, Eliot T / Manning, H Charles / Hight, Matthew R / Schulte, Michael L / Watt, Kimberly R / Ayers, G Daniel / Wolf, Melissa M / Andrejeva, Gabriela / Rathmell, Jeffrey C / Franklin, Jeffrey L / Coffey, Robert J

Cellular and molecular gastroenterology and hepatology

2018 Volume 5, Issue 4, Page(s) 627–629.e6

Language	English
Publishing date	2018
Publishing country	United States
Document type	Journal Article
ISSN	2352-345X
ISSN	2352-345X
DOI	10.1016/j.jcmgh.2018.01.013
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Article ; Online: Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism.

Cell

2018 Volume 175, Issue 7, Page(s) 1780–1795.e19

Abstract: Activated T cells differentiate into functional subsets with distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and epigenetic reactions. Here, we identify a key role for GLS ... ...

Abstract	Activated T cells differentiate into functional subsets with distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and epigenetic reactions. Here, we identify a key role for GLS in T cell activation and specification. Though GLS deficiency diminished initial T cell activation and proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet to promote differentiation and effector function of CD4 Th1 and CD8 CTL cells. This was associated with altered chromatin accessibility and gene expression, including decreased PIK3IP1 in Th1 cells that sensitized to IL-2-mediated mTORC1 signaling. In vivo, GLS null T cells failed to drive Th17-inflammatory diseases, and Th1 cells had initially elevated function but exhausted over time. Transient GLS inhibition, however, led to increased Th1 and CTL T cell numbers. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/cytology ; CD8-Positive T-Lymphocytes/immunology ; Cell Differentiation/genetics ; Cell Differentiation/immunology ; Glutaminase/genetics ; Glutaminase/immunology ; Lymphocyte Activation ; Male ; Mice ; Mice, Transgenic ; Th1 Cells/cytology ; Th1 Cells/immunology ; Th17 Cells/cytology ; Th17 Cells/immunology
Chemical Substances	Glutaminase (EC 3.5.1.2)
Language	English
Publishing date	2018-11-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2018.10.001
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