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Article ; Online: From patient tissue correlates to molecular mechanisms of cancer immune evasion: the emerging role of CD58 and PD-L1 co-regulation via CMTM6.

Melms, Johannes C / Ho, Patricia / Rogava, Meri / Izar, Benjamin

2023 Volume 25, Issue 1, Page(s) 82–84

Abstract: Immune evasion is a hallmark of cancer, yet the underlying mechanisms are often unknown in many patients. Using single-cell transcriptomics analysis, we previously identified the co-stimulator CD58 as part of a cancer cell-intrinsic immune checkpoint ... ...

Abstract	Immune evasion is a hallmark of cancer, yet the underlying mechanisms are often unknown in many patients. Using single-cell transcriptomics analysis, we previously identified the co-stimulator CD58 as part of a cancer cell-intrinsic immune checkpoint resistance signature in patient melanoma tissue. We subsequently validated CD58 loss as a driver of immune evasion using a patient-derived co-culture model of cancer and cytotoxic tumor-infiltrating lymphocytes in a pooled single-cell perturbation experiment, where we additionally observed concurrent upregulation of PD-L1 protein expression in melanoma cells with CD58 loss. In our most recent study, we uncovered the mechanisms of immune evasion mediated by CD58 loss, including impaired T cell activation and infiltration within tumors, as well as inhibitory signaling by PD-L1 via a shared regulator, CMTM6. Thus, cancer cell-intrinsic reduction of CD58 represents a multi-faceted determinant of immune evasion. Furthermore, its reciprocal interaction with PD-L1 via CMTM6 provides critical insights into how co-inhibitory and co-stimulatory immune cues are regulated.
MeSH term(s)	Humans ; B7-H1 Antigen/genetics ; Melanoma/genetics ; Immune Evasion ; Cell Line, Tumor ; Signal Transduction
Chemical Substances	B7-H1 Antigen
Language	English
Publishing date	2023-12-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2060566-3
ISSN	1476-5470 ; 1466-4879
ISSN (online)	1476-5470
ISSN	1466-4879
DOI	10.1038/s41435-023-00224-9
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Article ; Online: CXCR3: Here to stay to enhance cancer immunotherapy?

Rogava, Meri / Izar, Benjamin

EBioMedicine

2019 Volume 49, Page(s) 11–12

MeSH term(s)	Biomarkers ; Humans ; Immunomodulation ; Immunotherapy ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/therapy ; Receptors, CXCR3/metabolism ; Treatment Outcome
Chemical Substances	Biomarkers ; CXCR3 protein, human ; Receptors, CXCR3
Language	English
Publishing date	2019-11-02
Publishing country	Netherlands
Document type	Letter
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2019.09.044
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Article: KLRG1 marks tumor-infiltrating CD4 T cell subsets associated with tumor progression and immunotherapy response.

Ager, Casey R / Zhang, Mingxuan / Chaimowitz, Matthew / Bansal, Shruti / Obradovic, Aleksandar / Rogava, Meri / Melms, Johannes C / McCann, Patrick / Spina, Catherine / Drake, Charles G / Dallos, Matthew C / Izar, Benjamin

bioRxiv : the preprint server for biology

2023

Abstract: Current methods for biomarker discovery and target identification in immuno-oncology rely on static snapshots of tumor immunity. To thoroughly characterize the temporal nature of antitumor immune responses, we developed a 34-parameter spectral flow ... ...

Abstract	Current methods for biomarker discovery and target identification in immuno-oncology rely on static snapshots of tumor immunity. To thoroughly characterize the temporal nature of antitumor immune responses, we developed a 34-parameter spectral flow cytometry panel and performed high-throughput analyses in critical contexts. We leveraged two distinct preclinical models that recapitulate cancer immunoediting (NPK-C1) and immune checkpoint blockade (ICB) response (MC38), respectively, and profiled multiple relevant tissues at and around key inflection points of immune surveillance and escape and/or ICB response. Machine learning-driven data analysis revealed a pattern of KLRG1 expression that uniquely identified intratumoral effector CD4 T cell populations that constitutively associate with tumor burden across tumor models, and are lost in tumors undergoing regression in response to ICB. Similarly, a Helios
Language	English
Publishing date	2023-01-02
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.01.522340
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Article ; Online: KLRG1 marks tumor-infiltrating CD4 T cell subsets associated with tumor progression and immunotherapy response.

Ager, Casey R / Zhang, Mingxuan / Chaimowitz, Matthew / Bansal, Shruti / Tagore, Somnath / Obradovic, Aleksandar / Jugler, Collin / Rogava, Meri / Melms, Johannes C / McCann, Patrick / Spina, Catherine / Drake, Charles G / Dallos, Matthew C / Izar, Benjamin

Journal for immunotherapy of cancer

2023 Volume 11, Issue 9

Abstract	Current methods for biomarker discovery and target identification in immuno-oncology rely on static snapshots of tumor immunity. To thoroughly characterize the temporal nature of antitumor immune responses, we developed a 34-parameter spectral flow cytometry panel and performed high-throughput analyses in critical contexts. We leveraged two distinct preclinical models that recapitulate cancer immunoediting (NPK-C1) and immune checkpoint blockade (ICB) response (MC38), respectively, and profiled multiple relevant tissues at and around key inflection points of immune surveillance and escape and/or ICB response. Machine learning-driven data analysis revealed a pattern of KLRG1 expression that uniquely identified intratumoral effector CD4 T cell populations that constitutively associate with tumor burden across tumor models, and are lost in tumors undergoing regression in response to ICB. Similarly, a Helios
MeSH term(s)	Humans ; CD4-Positive T-Lymphocytes ; T-Lymphocyte Subsets ; Carcinoma, Renal Cell ; Kidney Neoplasms ; Immunotherapy ; Biomarkers ; Receptors, Immunologic ; Lectins, C-Type
Chemical Substances	Biomarkers ; KLRG1 protein, human ; Receptors, Immunologic ; Lectins, C-Type
Language	English
Publishing date	2023-08-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2023-006782
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Article ; Online: Tumor cell intrinsic Toll-like receptor 4 signaling promotes melanoma progression and metastatic dissemination.

Rogava, Meri / Braun, Andreas Dominik / van der Sluis, Tetje Cornelia / Shridhar, Naveen / Tüting, Thomas / Gaffal, Evelyn

International journal of cancer

2021 Volume 150, Issue 1, Page(s) 142–151

Abstract: Most melanoma-associated deaths result from the early development of metastasis. Toll-like receptor 4 (TLR4) expression on nontumor cells is well known to contribute to tumor development and metastatic progression. The role of TLR4 expression on tumor ... ...

Abstract	Most melanoma-associated deaths result from the early development of metastasis. Toll-like receptor 4 (TLR4) expression on nontumor cells is well known to contribute to tumor development and metastatic progression. The role of TLR4 expression on tumor cells however is less well understood. Here we describe TLR4 as a driver of tumor progression and metastatic spread of melanoma cells by employing a transplantable mouse melanoma model. HCmel12 melanoma cells lacking functional TLR4 showed increased sensitivity to tumor necrosis factor α induced cell killing in vitro compared to cells with intact TLR4. Interestingly, TLR4 knockout melanoma cells also showed impaired migratory capacity in vitro and a significantly reduced ability to metastasize to the lungs after subcutaneous transplantation in vivo. Finally, we demonstrate that activation of TLR4 also promotes migration in a subset of human melanoma cell lines. Our work describes TLR4 as an important mediator of melanoma migration and metastasis and provides a rationale for therapeutic inhibition of TLR4 in melanoma.
MeSH term(s)	Animals ; Apoptosis ; CRISPR-Cas Systems ; Cell Movement ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/secondary ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Mice ; Mice, Inbred C57BL ; Toll-Like Receptor 4/antagonists & inhibitors ; Toll-Like Receptor 4/genetics ; Toll-Like Receptor 4/metabolism ; Tumor Cells, Cultured
Chemical Substances	Toll-Like Receptor 4
Language	English
Publishing date	2021-09-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218257-9
ISSN	1097-0215 ; 0020-7136
ISSN (online)	1097-0215
ISSN	0020-7136
DOI	10.1002/ijc.33804
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Zs.A 478: 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)
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Article: The myeloid cell type I IFN system promotes antitumor immunity over pro-tumoral inflammation in cancer T-cell therapy.

Ruotsalainen, Janne / Lopez-Ramos, Dorys / Rogava, Meri / Shridhar, Naveen / Glodde, Nicole / Gaffal, Evelyn / Hölzel, Michael / Bald, Tobias / Tüting, Thomas

Clinical & translational immunology

2021 Volume 10, Issue 4, Page(s) e1276

Abstract: Objectives: Type I interferons are evolutionally conserved cytokines, with broad antimicrobial and immunoregulatory functions. Despite well-characterised role in spontaneous cancer immunosurveillance, the function of type I IFNs in cancer immunotherapy ... ...

Abstract	Objectives: Type I interferons are evolutionally conserved cytokines, with broad antimicrobial and immunoregulatory functions. Despite well-characterised role in spontaneous cancer immunosurveillance, the function of type I IFNs in cancer immunotherapy remains incompletely understood. Methods: We utilised genetic mouse models to explore the role of the type I IFN system in CD8 Results: The therapeutic efficacy of adoptively transferred T cells was found to depend on a functional type I IFN system in myeloid immune cells. Compromised type I IFN signalling in myeloid immune cells did not prevent expansion, tumor infiltration or effector function of melanoma-specific Pmel-1 CD8 Conclusion: Our results substantiate a complex and plastic phenotypic interconnection between melanoma and myeloid cells in the context of T-cell immunotherapy. Type I IFN signalling in myeloid cells was identified as a key regulator of the balance between antitumor immunity and disease-promoting inflammation, thus supporting the development of novel combinatorial immunotherapies targeting this immune cell compartment.
Language	English
Publishing date	2021-04-29
Publishing country	Australia
Document type	Journal Article
ZDB-ID	2694482-0
ISSN	2050-0068
ISSN	2050-0068
DOI	10.1002/cti2.1276
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Article ; Online: Author Correction: Neoadjuvant durvalumab plus radiation versus durvalumab alone in stages I-III non-small cell lung cancer: survival outcomes and molecular correlates of a randomized phase II trial.

Nature communications

2024 Volume 15, Issue 1, Page(s) 225

Language	English
Publishing date	2024-01-03
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-44575-3
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Article ; Online: Systematic elucidation and pharmacological targeting of tumor-infiltrating regulatory T cell master regulators.

Cancer cell

2023 Volume 41, Issue 5, Page(s) 933–949.e11

Abstract: Due to their immunosuppressive role, tumor-infiltrating regulatory T cells (TI-Tregs) represent attractive immuno-oncology targets. Analysis of TI vs. peripheral Tregs (P-Tregs) from 36 patients, across four malignancies, identified 17 candidate master ... ...

Abstract	Due to their immunosuppressive role, tumor-infiltrating regulatory T cells (TI-Tregs) represent attractive immuno-oncology targets. Analysis of TI vs. peripheral Tregs (P-Tregs) from 36 patients, across four malignancies, identified 17 candidate master regulators (MRs) as mechanistic determinants of TI-Treg transcriptional state. Pooled CRISPR-Cas9 screening in vivo, using a chimeric hematopoietic stem cell transplant model, confirmed the essentiality of eight MRs in TI-Treg recruitment and/or retention without affecting other T cell subtypes, and targeting one of the most significant MRs (Trps1) by CRISPR KO significantly reduced ectopic tumor growth. Analysis of drugs capable of inverting TI-Treg MR activity identified low-dose gemcitabine as the top prediction. Indeed, gemcitabine treatment inhibited tumor growth in immunocompetent but not immunocompromised allografts, increased anti-PD-1 efficacy, and depleted MR-expressing TI-Tregs in vivo. This study provides key insight into Treg signaling, specifically in the context of cancer, and a generalizable strategy to systematically elucidate and target MR proteins in immunosuppressive subpopulations.
MeSH term(s)	Humans ; T-Lymphocytes, Regulatory/metabolism ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Proteins/metabolism ; Lymphocytes, Tumor-Infiltrating/metabolism ; Repressor Proteins/metabolism
Chemical Substances	Proteins ; TRPS1 protein, human ; Repressor Proteins
Language	English
Publishing date	2023-04-27
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2023.04.003
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Zs.A 5650: 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.MG 104: Show issues

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Article ; Online: Neoadjuvant durvalumab plus radiation versus durvalumab alone in stages I-III non-small cell lung cancer: survival outcomes and molecular correlates of a randomized phase II trial.

Nature communications

2023 Volume 14, Issue 1, Page(s) 8435

Abstract: We previously reported the results of a randomized phase II trial (NCT02904954) in patients with early-stage non-small cell lung cancer (NSCLC) who were treated with either two preoperative cycles of the anti-PD-L1 antibody durvalumab alone or combined ... ...

Abstract	We previously reported the results of a randomized phase II trial (NCT02904954) in patients with early-stage non-small cell lung cancer (NSCLC) who were treated with either two preoperative cycles of the anti-PD-L1 antibody durvalumab alone or combined with immunomodulatory doses of stereotactic radiation (DRT). The trial met its primary endpoint of major pathological response, which was significantly higher following DRT with no new safety signals. Here, we report on the prespecified secondary endpoint of disease-free survival (DFS) regardless of treatment assignment and the prespecified exploratory analysis of DFS in each arm of the trial. DFS at 2 and 3 years across patients in both arms of the trial were 73% (95% CI: 62.1-84.5) and 65% (95% CI: 52.5-76.9) respectively. For the exploratory endpoint of DFS in each arm of the trial, three-year DFS was 63% (95% CI: 46.0-80.4) in the durvalumab monotherapy arm compared to 67% (95% CI: 49.6-83.4) in the dual therapy arm. In addition, we report post hoc exploratory analysis of progression-free survival as well as molecular correlates of response and recurrence through high-plex immunophenotyping of sequentially collected peripheral blood and gene expression profiles from resected tumors in both treatment arms. Together, our results contribute to the evolving landscape of neoadjuvant treatment regimens for NSCLC and identify easily measurable potential biomarkers of response and recurrence.
MeSH term(s)	Humans ; Antibodies, Monoclonal/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Lung Neoplasms/drug therapy ; Neoadjuvant Therapy ; Small Cell Lung Carcinoma/drug therapy ; Randomized Controlled Trials as Topic ; Clinical Trials, Phase II as Topic
Chemical Substances	Antibodies, Monoclonal ; durvalumab (28X28X9OKV)
Language	English
Publishing date	2023-12-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-44195-x
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Article ; Online: A stochastic model for immunotherapy of cancer.

Baar, Martina / Coquille, Loren / Mayer, Hannah / Hölzel, Michael / Rogava, Meri / Tüting, Thomas / Bovier, Anton

Scientific reports

2016 Volume 6, Page(s) 24169

Abstract: We propose an extension of a standard stochastic individual-based model in population dynamics which broadens the range of biological applications. Our primary motivation is modelling of immunotherapy of malignant tumours. In this context the different ... ...

Abstract	We propose an extension of a standard stochastic individual-based model in population dynamics which broadens the range of biological applications. Our primary motivation is modelling of immunotherapy of malignant tumours. In this context the different actors, T-cells, cytokines or cancer cells, are modelled as single particles (individuals) in the stochastic system. The main expansions of the model are distinguishing cancer cells by phenotype and genotype, including environment-dependent phenotypic plasticity that does not affect the genotype, taking into account the effects of therapy and introducing a competition term which lowers the reproduction rate of an individual in addition to the usual term that increases its death rate. We illustrate the new setup by using it to model various phenomena arising in immunotherapy. Our aim is twofold: on the one hand, we show that the interplay of genetic mutations and phenotypic switches on different timescales as well as the occurrence of metastability phenomena raise new mathematical challenges. On the other hand, we argue why understanding purely stochastic events (which cannot be obtained with deterministic models) may help to understand the resistance of tumours to therapeutic approaches and may have non-trivial consequences on tumour treatment protocols. This is supported through numerical simulations.
MeSH term(s)	Genotype ; Humans ; Immunotherapy ; Models, Theoretical ; Mutation ; Neoplasms/mortality ; Neoplasms/therapy ; Stochastic Processes
Language	English
Publishing date	2016-04-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep24169
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