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Article: Neuropeptide Y/Y5 Receptor Pathway Stimulates Neuroblastoma Cell Motility Through RhoA Activation.

Abualsaud, Nouran / Caprio, Lindsay / Galli, Susana / Krawczyk, Ewa / Alamri, Lamia / Zhu, Shiya / Gallicano, G Ian / Kitlinska, Joanna

Frontiers in cell and developmental biology

2021 Volume 8, Page(s) 627090

Abstract: Neuropeptide Y (NPY) has been implicated in the regulation of cellular motility under various physiological and pathological conditions, including cancer dissemination. Yet, the exact signaling pathways leading to these effects remain unknown. In a ... ...

Abstract	Neuropeptide Y (NPY) has been implicated in the regulation of cellular motility under various physiological and pathological conditions, including cancer dissemination. Yet, the exact signaling pathways leading to these effects remain unknown. In a pediatric malignancy, neuroblastoma (NB), high NPY release from tumor tissue associates with metastatic disease. Here, we have shown that NPY stimulates NB cell motility and invasiveness and acts as a chemotactic factor for NB cells. We have also identified the Y5 receptor (Y5R) as the main NPY receptor mediating these actions. In NB tissues and cell cultures, Y5R is highly expressed in migratory cells and accumulates in regions of high RhoA activity and dynamic cytoskeleton remodeling. Y5R stimulation activates RhoA and results in Y5R/RhoA-GTP interactions, as shown by pull-down and proximity ligation assays, respectively. This is the first demonstration of the role for the NPY/Y5R axis in RhoA activation and the subsequent cytoskeleton remodeling facilitating cell movement. These findings implicate Y5R as a target in anti-metastatic therapies for NB and other cancers expressing this receptor.
Language	English
Publishing date	2021-02-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2020.627090
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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: Multimodal single-cell and whole-genome sequencing of small, frozen clinical specimens.

Wang, Yiping / Fan, Joy Linyue / Melms, Johannes C / Amin, Amit Dipak / Georgis, Yohanna / Barrera, Irving / Ho, Patricia / Tagore, Somnath / Abril-Rodríguez, Gabriel / He, Siyu / Jin, Yinuo / Biermann, Jana / Hofree, Matan / Caprio, Lindsay / Berhe, Simon / Khan, Shaheer A / Henick, Brian S / Ribas, Antoni / Macosko, Evan Z /

Chen, Fei / Taylor, Alison M / Schwartz, Gary K / Carvajal, Richard D / Azizi, Elham / Izar, Benjamin

Nature genetics

2023 Volume 55, Issue 1, Page(s) 19–25

Abstract: Single-cell genomics enables dissection of tumor heterogeneity and molecular underpinnings of drug response at an unprecedented ... ...

Abstract	Single-cell genomics enables dissection of tumor heterogeneity and molecular underpinnings of drug response at an unprecedented resolution
MeSH term(s)	Humans ; Genomics/methods ; Gene Expression Profiling/methods ; Neoplasms/genetics ; Sequence Analysis, RNA/methods ; Whole Genome Sequencing
Language	English
Publishing date	2023-01-09
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.
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-022-01268-9
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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: The CD58-CD2 axis is co-regulated with PD-L1 via CMTM6 and shapes anti-tumor immunity.

Ho, Patricia / Melms, Johannes C / Rogava, Meri / Frangieh, Chris J / Poźniak, Joanna / Shah, Shivem B / Walsh, Zachary / Kyrysyuk, Oleksandr / Amin, Amit Dipak / Caprio, Lindsay / Fullerton, Benjamin T / Soni, Rajesh Kumar / Ager, Casey R / Biermann, Jana / Wang, Yiping / Khosravi-Maharlooei, Mohsen / Zanetti, Giorgia / Mu, Michael / Fatima, Hijab /

Moore, Emily K / Vasan, Neil / Bakhoum, Samuel F / Reiner, Steven L / Bernatchez, Chantale / Sykes, Megan / Mace, Emily M / Wucherpfennig, Kai W / Schadendorf, Dirk / Bechter, Oliver / Shah, Parin / Schwartz, Gary K / Marine, Jean-Christophe / Izar, Benjamin

Cancer cell

2023 Volume 41, Issue 7, Page(s) 1207–1221.e12

Abstract: The cell-autonomous balance of immune-inhibitory and -stimulatory signals is a critical process in cancer immune evasion. Using patient-derived co-cultures, humanized mouse models, and single-cell RNA-sequencing of patient melanomas biopsied before and ... ...

Abstract	The cell-autonomous balance of immune-inhibitory and -stimulatory signals is a critical process in cancer immune evasion. Using patient-derived co-cultures, humanized mouse models, and single-cell RNA-sequencing of patient melanomas biopsied before and on immune checkpoint blockade, we find that intact cancer cell-intrinsic expression of CD58 and ligation to CD2 is required for anti-tumor immunity and is predictive of treatment response. Defects in this axis promote immune evasion through diminished T cell activation, impaired intratumoral T cell infiltration and proliferation, and concurrently increased PD-L1 protein stabilization. Through CRISPR-Cas9 and proteomics screens, we identify and validate CMTM6 as critical for CD58 stability and upregulation of PD-L1 upon CD58 loss. Competition between CD58 and PD-L1 for CMTM6 binding determines their rate of endosomal recycling over lysosomal degradation. Overall, we describe an underappreciated yet critical axis of cancer immunity and provide a molecular basis for how cancer cells balance immune inhibitory and stimulatory cues.
MeSH term(s)	Mice ; Animals ; B7-H1 Antigen/genetics ; T-Lymphocytes ; CD58 Antigens/chemistry ; CD58 Antigens/metabolism ; Melanoma/genetics ; Melanoma/metabolism ; Lymphocyte Activation
Chemical Substances	B7-H1 Antigen ; CD58 Antigens
Language	English
Publishing date	2023-06-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2023.05.014
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Article ; Online: Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation.

Rogava, Meri / Aprati, Tyler J / Chi, Wei-Yu / Melms, Johannes C / Hug, Clemens / Davis, Stephanie H / Earlie, Ethan M / Chung, Charlie / Deshmukh, Sachin K / Wu, Sharon / Sledge, George / Tang, Stephen / Ho, Patricia / Amin, Amit Dipak / Caprio, Lindsay / Gurjao, Carino / Tagore, Somnath / Ngo, Bryan / Lee, Michael J /

Zanetti, Giorgia / Wang, Yiping / Chen, Sean / Ge, William / Melo, Luiza Martins Nascentes / Allies, Gabriele / Rösler, Jonas / Gibney, Goeffrey T / Schmitz, Oliver J / Sykes, Megan / Creusot, Rémi J / Tüting, Thomas / Schadendorf, Dirk / Röcken, Martin / Eigentler, Thomas K / Molotkov, Andrei / Mintz, Akiva / Bakhoum, Samuel F / Beyaz, Semir / Cantley, Lewis C / Sorger, Peter K / Meckelmann, Sven W / Tasdogan, Alpaslan / Liu, David / Laughney, Ashley M / Izar, Benjamin

Nature cancer

2024 Volume 5, Issue 3, Page(s) 433–447

Abstract: Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR-Cas9 screens, we found that Pip4k2c loss conferred LM but had no ... ...

Abstract	Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR-Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis. We observed concordant changes in PIP4K2C expression and distinct metabolic changes in 3,511 patient melanomas, including primary tumors, LMs and lung metastases. We found that systemic PI3K inhibition exacerbated LM burden in mice injected with Pip4k2c-deficient cancer cells through host-mediated increase in hepatic insulin levels; however, this circuit could be broken by concurrent administration of an SGLT2 inhibitor or feeding of a ketogenic diet. Thus, this work demonstrates a rare example of metastatic organotropism through co-optation of physiological metabolic cues and proposes therapeutic avenues to counteract these mechanisms.
MeSH term(s)	Humans ; Mice ; Animals ; Proto-Oncogene Proteins c-akt/metabolism ; Phosphatidylinositol 3-Kinases ; Signal Transduction ; Liver Neoplasms ; Insulin ; Phosphotransferases (Alcohol Group Acceptor)/metabolism
Chemical Substances	Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Insulin ; Pip4k2c protein, mouse (EC 2.7.1.149) ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-)
Language	English
Publishing date	2024-01-29
Publishing country	England
Document type	Journal Article
ISSN	2662-1347
ISSN (online)	2662-1347
DOI	10.1038/s43018-023-00704-x
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Article ; Online: A Tumor Cell-Selective Inhibitor of Mitogen-Activated Protein Kinase Phosphatases Sensitizes Breast Cancer Cells to Lymphokine-Activated Killer Cell Activity.

Kaltenmeier, Christof T / Vollmer, Laura L / Vernetti, Lawrence A / Caprio, Lindsay / Davis, Keanu / Korotchenko, Vasiliy N / Day, Billy W / Tsang, Michael / Hulkower, Keren I / Lotze, Michael T / Vogt, Andreas

The Journal of pharmacology and experimental therapeutics

2017 Volume 361, Issue 1, Page(s) 39–50

Abstract: Dual specificity mitogen-activated protein kinase (MAPK) phosphatases [dual specificity phosphatase/MAP kinase phosphatase (DUSP-MKP)] have been hypothesized to maintain cancer cell survival by buffering excessive MAPK signaling caused by upstream ... ...

Abstract	Dual specificity mitogen-activated protein kinase (MAPK) phosphatases [dual specificity phosphatase/MAP kinase phosphatase (DUSP-MKP)] have been hypothesized to maintain cancer cell survival by buffering excessive MAPK signaling caused by upstream activating oncogenic products. A large and diverse body of literature suggests that genetic depletion of DUSP-MKPs can reduce tumorigenicity, suggesting that hyperactivating MAPK signaling by DUSP-MKP inhibitors could be a novel strategy to selectively affect the transformed phenotype. Through in vivo structure-activity relationship studies in transgenic zebrafish we recently identified a hyperactivator of fibroblast growth factor signaling [(E)-2-benzylidene-5-bromo-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI-215)] that is devoid of developmental toxicity and restores defective MAPK activity caused by overexpression of DUSP1 and DUSP6 in mammalian cells. Here, we hypothesized that BCI-215 could selectively affect survival of transformed cells. In MDA-MB-231 human breast cancer cells, BCI-215 inhibited cell motility, caused apoptosis but not primary necrosis, and sensitized cells to lymphokine-activated killer cell activity. Mechanistically, BCI-215 induced rapid and sustained phosphorylation of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) in the absence of reactive oxygen species, and its toxicity was partially rescued by inhibition of p38 but not JNK or ERK. BCI-215 also hyperactivated MKK4/SEK1, suggesting activation of stress responses. Kinase phosphorylation profiling documented BCI-215 selectively activated MAPKs and their downstream substrates, but not receptor tyrosine kinases, SRC family kinases, AKT, mTOR, or DNA damage pathways. Our findings support the hypothesis that BCI-215 causes selective cancer cell cytotoxicity in part through non-redox-mediated activation of MAPK signaling, and the findings also identify an intersection with immune cell killing that is worthy of further exploration.
MeSH term(s)	Animals ; Animals, Genetically Modified ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Breast Neoplasms/drug therapy ; Breast Neoplasms/immunology ; Breast Neoplasms/metabolism ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Female ; HeLa Cells ; Hepatocytes/drug effects ; Hepatocytes/immunology ; Hepatocytes/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors ; JNK Mitogen-Activated Protein Kinases/immunology ; JNK Mitogen-Activated Protein Kinases/metabolism ; Killer Cells, Lymphokine-Activated/drug effects ; Killer Cells, Lymphokine-Activated/immunology ; Killer Cells, Lymphokine-Activated/metabolism ; Mitogen-Activated Protein Kinase Phosphatases/antagonists & inhibitors ; Mitogen-Activated Protein Kinase Phosphatases/immunology ; Mitogen-Activated Protein Kinase Phosphatases/metabolism ; Rats ; Zebrafish
Chemical Substances	Antineoplastic Agents ; Enzyme Inhibitors ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase Phosphatases (EC 3.1.3.16)
Language	English
Publishing date	2017-02-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.116.239756
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Article: Dissecting the treatment-naive ecosystem of human melanoma brain metastasis

Biermann, Jana / Melms, Johannes C. / Amin, Amit Dipak / Wang, Yiping / Caprio, Lindsay A. / Karz, Alcida / Tagore, Somnath / Barrera, Irving / Ibarra-Arellano, Miguel A. / Andreatta, Massimo / Fullerton, Benjamin T. / Gretarsson, Kristjan H. / Sahu, Varun / Mangipudy, Vaibhav S. / Nguyen, Trang T.T. / Nair, Ajay / Rogava, Meri / Ho, Patricia / Koch, Peter D. /

Banu, Matei / Humala, Nelson / Mahajan, Aayushi / Walsh, Zachary H. / Shah, Shivem B. / Vaccaro, Daniel H. / Caldwell, Blake / Mu, Michael / Wünnemann, Florian / Chazotte, Margot / Berhe, Simon / Luoma, Adrienne M. / Driver, Joseph / Ingham, Matthew / Khan, Shaheer A. / Rapisuwon, Suthee / Slingluff, Craig L. / Eigentler, Thomas / Röcken, Martin / Carvajal, Richard / Atkins, Michael B. / Davies, Michael A. / Agustinus, Albert / Bakhoum, Samuel F. / Azizi, Elham / Siegelin, Markus / Lu, Chao / Carmona, Santiago J. / Hibshoosh, Hanina / Ribas, Antoni / Canoll, Peter / Bruce, Jeffrey N. / Bi, Wenya Linda / Agrawal, Praveen / Schapiro, Denis / Hernando, Eva / Macosko, Evan Z. / Chen, Fei / Schwartz, Gary K. / Izar, Benjamin

Cell. 2022 July 07, v. 185, no. 14

2022

Abstract: Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial ... ...

Abstract	Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBMs were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX⁺CD8⁺ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.
Keywords	T-lymphocytes ; brain ; cell differentiation ; ecosystems ; geography ; humans ; immune evasion ; macrophages ; melanoma ; metastasis ; patients ; proteomics ; sequence analysis ; transcriptomics ; xenotransplantation
Language	English
Dates of publication	2022-0707
Size	p. 2591-2608.e30.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2022.06.007
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Article ; Online: Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.

Biermann, Jana / Melms, Johannes C / Amin, Amit Dipak / Wang, Yiping / Caprio, Lindsay A / Karz, Alcida / Tagore, Somnath / Barrera, Irving / Ibarra-Arellano, Miguel A / Andreatta, Massimo / Fullerton, Benjamin T / Gretarsson, Kristjan H / Sahu, Varun / Mangipudy, Vaibhav S / Nguyen, Trang T T / Nair, Ajay / Rogava, Meri / Ho, Patricia / Koch, Peter D /

Banu, Matei / Humala, Nelson / Mahajan, Aayushi / Walsh, Zachary H / Shah, Shivem B / Vaccaro, Daniel H / Caldwell, Blake / Mu, Michael / Wünnemann, Florian / Chazotte, Margot / Berhe, Simon / Luoma, Adrienne M / Driver, Joseph / Ingham, Matthew / Khan, Shaheer A / Rapisuwon, Suthee / Slingluff, Craig L / Eigentler, Thomas / Röcken, Martin / Carvajal, Richard / Atkins, Michael B / Davies, Michael A / Agustinus, Albert / Bakhoum, Samuel F / Azizi, Elham / Siegelin, Markus / Lu, Chao / Carmona, Santiago J / Hibshoosh, Hanina / Ribas, Antoni / Canoll, Peter / Bruce, Jeffrey N / Bi, Wenya Linda / Agrawal, Praveen / Schapiro, Denis / Hernando, Eva / Macosko, Evan Z / Chen, Fei / Schwartz, Gary K / Izar, Benjamin

Cell

2022 Volume 185, Issue 14, Page(s) 2591–2608.e30

Abstract	Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX
MeSH term(s)	Brain Neoplasms/drug therapy ; Brain Neoplasms/secondary ; CD8-Positive T-Lymphocytes/pathology ; Ecosystem ; Humans ; Melanoma ; RNA-Seq
Language	English
Publishing date	2022-07-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; 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.2022.06.007
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