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Article ; Online: Defining and using immune archetypes to classify and treat cancer.

Combes, Alexis J / Samad, Bushra / Krummel, Matthew F

2023 Volume 23, Issue 7, Page(s) 491–505

Abstract: Tumours are surrounded by a host immune system that can suppress or promote tumour growth. The tumour microenvironment (TME) has often been framed as a singular entity, suggesting a single type of immune state that is defective and in need of therapeutic ...

Abstract	Tumours are surrounded by a host immune system that can suppress or promote tumour growth. The tumour microenvironment (TME) has often been framed as a singular entity, suggesting a single type of immune state that is defective and in need of therapeutic intervention. By contrast, the past few years have highlighted a plurality of immune states that can surround tumours. In this Perspective, we suggest that different TMEs have 'archetypal' qualities across all cancers - characteristic and repeating collections of cells and gene-expression profiles at the level of the bulk tumour. We discuss many studies that together support a view that tumours typically draw from a finite number (around 12) of 'dominant' immune archetypes. In considering the likely evolutionary origin and roles of these archetypes, their associated TMEs can be predicted to have specific vulnerabilities that can be leveraged as targets for cancer treatment with expected and addressable adverse effects for patients.
MeSH term(s)	Humans ; Neoplasms/therapy ; Neoplasms/drug therapy ; Tumor Microenvironment
Language	English
Publishing date	2023-06-05
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2062767-1
ISSN	1474-1768 ; 1474-175X
ISSN (online)	1474-1768
ISSN	1474-175X
DOI	10.1038/s41568-023-00578-2
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Article: Critical role of CD206+ macrophages in organizing anti-tumor immunity.

Ray, Arja / Hu, Kenneth H / Kersten, Kelly / Kuhn, Nicholas F / Samad, Bushra / Combes, Alexis J / Krummel, Matthew F

bioRxiv : the preprint server for biology

2023

Abstract: Tumor-associated macrophages (TAMs) are frequently and simplistically categorized as immunosuppressive, and one molecule prominently used to highlight their so-called 'M2' state is the surface protein CD206. However, direct evidence of the impact of ... ...

Abstract	Tumor-associated macrophages (TAMs) are frequently and simplistically categorized as immunosuppressive, and one molecule prominently used to highlight their so-called 'M2' state is the surface protein CD206. However, direct evidence of the impact of macrophages remains impaired by the lack of sufficiently penetrant and specific tools to manipulate them in vivo. We thus made a novel conditional CD206 knock-in mouse to specifically visualize and/or deplete these TAMs. Early depletion of CD206+ macrophages and monocytes (here, 'MonoMacs') strikingly led to an indirect loss of a key anti-tumor network of NK cells, conventional type I dendritic cells (cDC1) and CD8 T cells. Among myeloid cells, we found that the CD206+ TAMs are the primary producers of CXCL9, the well-established chemoattractant for CXCR3-expressing NK and CD8 T cells. In contrast, a population of stress-responsive TAMs ("Hypoxic" or
Language	English
Publishing date	2023-11-02
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.31.560822
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Article: Lack of TGFβ signaling competency predicts conversion of immune poor cancer to immune rich and response to checkpoint blockade.

Moore, Jade / Gkantalis, Jim / Guix, Ines / Chou, William / Yuen, Kobe / Lazar, Ann A / Spitzer, Mathew / Combes, Alexis J / Barcellos-Hoff, Mary Helen

bioRxiv : the preprint server for biology

2024

Abstract: Background: Transforming growth factor beta (TGFβ) is well-recognized as an immunosuppressive player in the tumor microenvironment but also has a significant impact on cancer cell phenotypes. Loss of TGFβ signaling impairs DNA repair competency, which ... ...

Abstract	Background: Transforming growth factor beta (TGFβ) is well-recognized as an immunosuppressive player in the tumor microenvironment but also has a significant impact on cancer cell phenotypes. Loss of TGFβ signaling impairs DNA repair competency, which is described by a transcriptomic score, βAlt. Cancers with high βAlt have more genomic damage and are more responsive to genotoxic therapy. The growing appreciation that cancer DNA repair deficits are important determinants of immune response prompted us to investigate βAlt's association with response to immune checkpoint blockade (ICB). We predicted that high βAlt tumors would be infiltrated with lymphocytes because of DNA damage burden and hence responsive to ICB. Methods: We analyzed public transcriptomic data from clinical trials and preclinical models using transcriptomic signatures of TGFβ targets, DNA repair genes, tumor educated immune cells and interferon. A high βAlt, immune poor mammary tumor derived transplant model resistant to programmed death ligand 1 (PD-L1) antibodies was studied using multispectral flow cytometry to interrogate the immune system. Results: Metastatic bladder patients in IMvigor 210 who responded to ICB had significantly increased βAlt scores and experienced significantly longer overall survival compared to those with low βAlt scores (hazard ratio 0.62, Conclusions: Our studies confirm βAlt as a biomarker that predicts response to ICB in immune poor cancers., which has implications for the development of therapeutic strategies to increase the number of cancer patients who will benefit from immunotherapy.
Language	English
Publishing date	2024-03-08
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.06.583752
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Article ; Online: Macrophage and CD8 T cell discordance are associated with acute lung allograft dysfunction progression.

Calabrese, Daniel R / Ekstrand, Christina A / Yellamilli, Shivaram / Singer, Jonathan P / Hays, Steven R / Leard, Lorriana E / Shah, Rupal J / Venado, Aida / Kolaitis, Nicholas A / Perez, Alyssa / Combes, Alexis / Greenland, John R

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation

2024

Abstract: Background: Acute lung allograft dysfunction (ALAD) is an imprecise syndrome denoting concern for the onset of chronic lung allograft dysfunction (CLAD). Mechanistic biomarkers are needed that stratify risk of ALAD progression to CLAD. We hypothesized ... ...

Abstract	Background: Acute lung allograft dysfunction (ALAD) is an imprecise syndrome denoting concern for the onset of chronic lung allograft dysfunction (CLAD). Mechanistic biomarkers are needed that stratify risk of ALAD progression to CLAD. We hypothesized that single cell investigation of bronchoalveolar lavage (BAL) cells at the time of ALAD would identify immune cells linked to progressive graft dysfunction. Methods: We prospectively collected BAL from consenting lung transplant recipients for single cell RNA sequencing. ALAD was defined by a ≥10% decrease in FEV Results: BAL was assessed for 17 ALAD cases with subsequent decline (ALAD declined), 13 ALAD cases that resolved (ALAD recovered), and 15 cases with stable lung function. We observed broad differences in frequencies of the 26 unique cell populations across groups (p = 0.02). A CD8 T cell (p = 0.04) and a macrophage cluster (p = 0.01) best identified ALAD declined from the ALAD recovered and stable groups. This macrophage cluster was distinguished by an anti-inflammatory signature and the CD8 T cell cluster resembled a Tissue Resident Memory subset. Anti-inflammatory macrophages signaled to activated CD8 T cells via class I HLA, fibronectin, and galectin pathways (p < 0.05 for each). Recipients with discordance between these cells had a nearly 5-fold increased risk of severe graft dysfunction or death (HR 4.6, 95% CI 1.1-19.2, adjusted p = 0.03). We validated these key findings in 2 public lung transplant genomic datasets. Conclusions: BAL anti-inflammatory macrophages may protect against CLAD by suppressing CD8 T cells. These populations merit functional and longitudinal assessment in additional cohorts.
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	1062522-7
ISSN	1557-3117 ; 1053-2498
ISSN (online)	1557-3117
ISSN	1053-2498
DOI	10.1016/j.healun.2024.02.007
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Zs.A 2056: Show issues

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Article: Decoding functional hematopoietic progenitor cells in the adult human lung.

Conrad, Catharina / Magnen, Melia / Tsui, Jessica / Wismer, Harrison / Naser, Mohammad / Venkataramani, Urmila / Samad, Bushra / Cleary, Simon J / Qiu, Longhui / Tian, Jennifer J / De Giovanni, Marco / Mende, Nicole / Passegue, Emmanuelle / Laurenti, Elisa / Combes, Alexis J / Looney, Mark R

Research square

2024

Abstract: The bone marrow is the main site of blood cell production in adults, however, rare pools of hematopoietic stem and progenitor cells with self-renewal and differentiation potential have been found in extramedullary organs. The lung is primarily known for ... ...

Abstract	The bone marrow is the main site of blood cell production in adults, however, rare pools of hematopoietic stem and progenitor cells with self-renewal and differentiation potential have been found in extramedullary organs. The lung is primarily known for its role in gas exchange but has recently been described as a site of blood production in mice. Here, we show that functional hematopoietic precursors reside in the extravascular spaces of the human lung, at a frequency similar to the bone marrow, and are capable of proliferation and engraftment. The organ-specific gene signature of pulmonary and medullary CD34
Language	English
Publishing date	2024-02-16
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3576483/v2
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Article ; Online: Archetypes of checkpoint-responsive immunity.

Im, Kwok / Combes, Alexis J / Spitzer, Matthew H / Satpathy, Ansuman T / Krummel, Matthew F

Trends in immunology

2021 Volume 42, Issue 11, Page(s) 960–974

Abstract: Responsiveness to immune checkpoint blockade (ICB) therapy in cancer is currently predicted by disparate individual measures - with varying degrees of accuracy - including tumor mutation burden, tumor-infiltrating T cell densities, dendritic cell ... ...

Abstract	Responsiveness to immune checkpoint blockade (ICB) therapy in cancer is currently predicted by disparate individual measures - with varying degrees of accuracy - including tumor mutation burden, tumor-infiltrating T cell densities, dendritic cell frequencies, and the expression of checkpoint ligands. We propose that many of these individual parameters are linked, forming two distinct 'reactive' immune archetypes - collections of cells and gene expression - in ICB-responsive patients. We hypothesize that these are 'seeds' of antitumor immunity and are supported by specific elements of the tumor microenvironment (TME) and by actions of the microbiome. Although removing 'immunosuppressive' factors in the TME is important, understanding and parsing reactive immunity is crucial for optimal prognosis and for engaging this biology with candidate therapies to increase tumor cure rates.
MeSH term(s)	Biomarkers, Tumor/metabolism ; Humans ; Neoplasms/therapy ; Prognosis ; T-Lymphocytes ; Tumor Microenvironment
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2021-10-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2036831-8
ISSN	1471-4981 ; 1471-4906
ISSN (online)	1471-4981
ISSN	1471-4906
DOI	10.1016/j.it.2021.09.007
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Zs.A 1601: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 2: Show issues

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Article: Tumor cell heterogeneity drives spatial organization of the intratumoral immune response in squamous cell skin carcinoma.

Tanaka, Miho / Lum, Lotus / Hu, Kenneth / Ledezma-Soto, Cecilia / Samad, Bushra / Superville, Daphne / Ng, Kenneth / Adams, Zoe / Kersten, Kelly / Fong, Lawrence / Combes, Alexis J / Krummel, Matthew / Reeves, Melissa

bioRxiv : the preprint server for biology

2023

Abstract: Intratumoral heterogeneity (ITH)-defined as genetic and cellular diversity within a tumor-is linked to failure of immunotherapy and an inferior anti-tumor immune response. The underlying mechanism of this association is unknown. To address this question, ...

Abstract	Intratumoral heterogeneity (ITH)-defined as genetic and cellular diversity within a tumor-is linked to failure of immunotherapy and an inferior anti-tumor immune response. The underlying mechanism of this association is unknown. To address this question, we modeled heterogeneous tumors comprised of a pro-inflammatory ("hot") and an immunosuppressive ("cold") tumor population, labeled with YFP and RFP tags respectively to enable precise spatial tracking. The resulting mixed-population tumors exhibited distinct regions comprised of YFP
Language	English
Publishing date	2023-06-21
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.25.538140
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Article ; Online: Polyunsaturated Fatty Acid-Bound α-Fetoprotein Promotes Immune Suppression by Altering Human Dendritic Cell Metabolism.

Munson, Paul V / Adamik, Juraj / Hartmann, Felix J / Favaro, Patricia M B / Ho, Daniel / Bendall, Sean C / Combes, Alexis J / Krummel, Matthew F / Zhang, Karen / Kelley, Robin K / Butterfield, Lisa H

Cancer research

2023 Volume 83, Issue 9, Page(s) 1543–1557

Abstract: α-Fetoprotein (AFP) is expressed by stem-like and poor outcome hepatocellular cancer tumors and is a clinical tumor biomarker. AFP has been demonstrated to inhibit dendritic cell (DC) differentiation and maturation and to block oxidative phosphorylation. ...

Abstract	α-Fetoprotein (AFP) is expressed by stem-like and poor outcome hepatocellular cancer tumors and is a clinical tumor biomarker. AFP has been demonstrated to inhibit dendritic cell (DC) differentiation and maturation and to block oxidative phosphorylation. To identify the critical metabolic pathways leading to human DC functional suppression, here, we used two recently described single-cell profiling methods, scMEP (single-cell metabolic profiling) and SCENITH (single-cell energetic metabolism by profiling translation inhibition). Glycolytic capacity and glucose dependence of DCs were significantly increased by tumor-derived, but not normal cord blood-derived, AFP, leading to increased glucose uptake and lactate secretion. Key molecules in the electron transport chain in particular were regulated by tumor-derived AFP. These metabolic changes occurred at mRNA and protein levels, with negative impact on DC stimulatory capacity. Tumor-derived AFP bound significantly more polyunsaturated fatty acids (PUFA) than cord blood-derived AFP. PUFAs bound to AFP increased metabolic skewing and promoted DC functional suppression. PUFAs inhibited DC differentiation in vitro, and ω-6 PUFAs conferred potent immunoregulation when bound to tumor-derived AFP. Together, these findings provide mechanistic insights into how AFP antagonizes the innate immune response to limit antitumor immunity. Significance: α-Fetoprotein (AFP) is a secreted tumor protein and biomarker with impact on immunity. Fatty acid-bound AFP promotes immune suppression by skewing human dendritic cell metabolism toward glycolysis and reduced immune stimulation.
MeSH term(s)	Humans ; alpha-Fetoproteins/genetics ; alpha-Fetoproteins/metabolism ; Liver Neoplasms/pathology ; Fatty Acids, Unsaturated/metabolism ; Fatty Acids/metabolism ; Biomarkers/metabolism ; Dendritic Cells
Chemical Substances	alpha-Fetoproteins ; Fatty Acids, Unsaturated ; Fatty Acids ; Biomarkers
Language	English
Publishing date	2023-02-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-22-3551
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Article ; Online: Transcriptional space-time mapping identifies concerted immune and stromal cell patterns and gene programs in wound healing and cancer.

Hu, Kenneth H / Kuhn, Nicholas F / Courau, Tristan / Tsui, Jessica / Samad, Bushra / Ha, Patrick / Kratz, Johannes R / Combes, Alexis J / Krummel, Matthew F

Cell stem cell

2023 Volume 30, Issue 6, Page(s) 885–903.e10

Abstract: Tissue repair responses in metazoans are highly coordinated by different cell types over space and time. However, comprehensive single-cell-based characterization covering this coordination is lacking. Here, we captured transcriptional states of single ... ...

Abstract	Tissue repair responses in metazoans are highly coordinated by different cell types over space and time. However, comprehensive single-cell-based characterization covering this coordination is lacking. Here, we captured transcriptional states of single cells over space and time during skin wound closure, revealing choreographed gene-expression profiles. We identified shared space-time patterns of cellular and gene program enrichment, which we call multicellular "movements" spanning multiple cell types. We validated some of the discovered space-time movements using large-volume imaging of cleared wounds and demonstrated the value of this analysis to predict "sender" and "receiver" gene programs in macrophages and fibroblasts. Finally, we tested the hypothesis that tumors are like "wounds that never heal" and found conserved wound healing movements in mouse melanoma and colorectal tumor models, as well as human tumor samples, revealing fundamental multicellular units of tissue biology for integrative studies.
MeSH term(s)	Mice ; Animals ; Humans ; Wound Healing/genetics ; Skin/pathology ; Neoplasms/pathology ; Macrophages/metabolism ; Fibroblasts/physiology ; Stromal Cells
Language	English
Publishing date	2023-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2375354-7
ISSN	1875-9777 ; 1934-5909
ISSN (online)	1875-9777
ISSN	1934-5909
DOI	10.1016/j.stem.2023.05.001
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Zs.A 6589: 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.MG 75: Show issues

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Article ; Online: Dysregulation of CD4

Journal for immunotherapy of cancer

2024 Volume 12, Issue 4

Abstract: Background: Colitis caused by checkpoint inhibitors (CPI) is frequent and is treated with empiric steroids, but CPI colitis mechanisms in steroid-experienced or refractory disease are unclear.: Methods: Using colon biopsies and blood from ... ...

Abstract	Background: Colitis caused by checkpoint inhibitors (CPI) is frequent and is treated with empiric steroids, but CPI colitis mechanisms in steroid-experienced or refractory disease are unclear. Methods: Using colon biopsies and blood from predominantly steroid-experienced CPI colitis patients, we performed multiplexed single-cell transcriptomics and proteomics to nominate contributing populations. Results: CPI colitis biopsies showed enrichment of CD4 Conclusions: These findings nominate CD4
MeSH term(s)	Humans ; CD8-Positive T-Lymphocytes ; Endothelial Cells ; Tumor Necrosis Factor Inhibitors ; Colitis/chemically induced ; Colitis/drug therapy ; CD4-Positive T-Lymphocytes ; Steroids/pharmacology ; Steroids/therapeutic use ; Stromal Cells
Chemical Substances	Tumor Necrosis Factor Inhibitors ; Steroids
Language	English
Publishing date	2024-04-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2023-008628
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