Multimodal Pooled Perturb-Cite-Seq Screens in Patient Models Define Mechanisms of Cancer Immune Evasion

In patient-derived melanoma cells and autologous tumor-infiltrating lymphocyte co-cultures, scientists profiled transcriptomes and 20 proteins in ~218,000 cells under ~750 perturbations associated with cancer cell-intrinsic immune checkpoint inhibitor resistance
[Nature Genetics]
Frangieh, C. J., Melms, J. C., Thakore, P. I., Geiger-Schuller, K. R., Ho, P., Luoma, A. M., Cleary, B., Jerby-Arnon, L., Malu, S., Cuoco, M. S., Zhao, M., Ager, C. R., Rogava, M., Hovey, L., Rotem, A., Bernatchez, C., Wucherpfennig, K. W., Johnson, B. E., Rozenblatt-Rosen, O., … Izar, B. (2021). Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion. Nature Genetics, 1–10. https://doi.org/10.1038/s41588-021-00779-1 Cite
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Transcriptional Network Constituted of CBP, Ku70, NOX2, and BAX Prevents the Cell Death of Necrosis, Paraptosis, and Apoptosis in Human Melanoma

Knocking down CREB-binding protein or Ku70 induced necrotic and paraptotic cell death as indicated by high-level intracellular reactive oxygen species, cytoplasmic vacuolization, and cell cycle arrest in the S phase.
[Cell Death Discovery]
Ding, L., Wen, Y., Zhang, X., Zhao, F., Lv, K., Shi, J., Shen, S., & Pan, X. (2021). Transcriptional network constituted of CBP, Ku70, NOX2, and BAX prevents the cell death of necrosis, paraptosis, and apoptosis in human melanoma. Cell Death Discovery, 7(1), 1–15. https://doi.org/10.1038/s41420-021-00417-z Cite
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Identification and Characterization of IMD-0354 as a Glutamine Carrier Protein Inhibitor in Melanoma

IMD-0354 was confirmed as a potent inhibitor of glutamine uptake that attained sustained low intracellular glutamine levels. Concomitant with its inhibition of glutamine uptake, IMD-0354 attenuated mTOR signaling, suppressed 2D and 3D growth of melanoma cells, and induced cell cycle arrest, autophagy and apoptosis.
[Molecular Cancer Therapeutics]
Feng, Y., Pathria, G., Heynen-Genel, S., Jackson, M. R., James, B., Yin, J., Scott, D. A., & Ronai, Z. A. (2021). Identification and Characterization of IMD-0354 as a Glutamine Carrier Protein Inhibitor in Melanoma. Molecular Cancer Therapeutics. https://doi.org/10.1158/1535-7163.MCT-20-0354 Cite
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Radiotherapy and Immunotherapy Converge on Elimination of Tumor-Promoting Erythroid Progenitor Cells through Adaptive Immunity

Scientists demonstrated that both local tumor ionizing radiation and anti–programmed death ligand 1 treatment decreased tumor-induced Ter cell abundance in the mouse spleen and ARTN secretion outside the irradiation field in an interferon- and CD8+ T cell–dependent manner.
[Science Translational Medicine]
Hou, Y., Liang, H. L., Yu, X., Liu, Z., Cao, X., Rao, E., Huang, X., Wang, L., Li, L., Bugno, J., Fu, Y., Chmura, S. J., Wu, W., Luo, S. Z., Zheng, W., Arina, A., Jutzy, J., McCall, A. R., Vokes, E. E., … Weichselbaum, R. R. (2021). Radiotherapy and immunotherapy converge on elimination of tumor-promoting erythroid progenitor cells through adaptive immunity. Science Translational Medicine, 13(582). https://doi.org/10.1126/scitranslmed.abb0130 Cite
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1,2, 4-Trimethoxybenzene Selectively Inhibits NLRP3 Inflammasome Activation and Attenuates Experimental Autoimmune Encephalomyelitis

Researchers showed that 1,2,4-TTB (1 mM) markedly suppressed nigericin- or ATP-induced NLRP3 inflammasome activation, thus decreased caspase-1 activation and IL-1β secretion in immortalized murine bone marrow-derived macrophages (iBMDMs) and in primary mouse microglia.
[Acta Pharmacologica Sinica]
1,2,4-Trimethoxybenzene selectively inhibits NLRP3 inflammasome activation and attenuates experimental autoimmune encephalomyelitis | Acta Pharmacologica Sinica. (n.d.). Retrieved March 1, 2021, from https://www.nature.com/articles/s41401-021-00613-8 Cite
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Screening of Metabolic Modulators Identifies New Strategies to Target Metabolic Reprogramming in Melanoma

To support the discovery of new drug candidates for melanoma, scientists examined 180 metabolic modulators, including phytochemicals and anti-diabetic compounds, for their growth-inhibitory activities against melanoma cells, alone and in combination with the BRAF inhibitor vemurafenib. 4-methylumbelliferone and ursolic acid, were subjected to validation and further characterization.
[Nature Communications]
Abildgaard, C., Rizza, S., Christiansen, H., Schmidt, S., Dahl, C., Abdul-Al, A., Christensen, A., Filomeni, G., & Guldberg, P. (2021). Screening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma. Scientific Reports, 11(1), 4390. https://doi.org/10.1038/s41598-021-83796-8 Cite
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Network Models of Primary Melanoma Microenvironments Identify Key Melanoma Regulators Underlying Prognosis

Seventeen key drivers of the gene subnetworks associated with poor prognosis, including the transcription factor ZNF180, are tested for their pro-tumorigenic effects in vitro. The anti-tumor effect of silencing ZNF180 is further validated using in vivo xenografts.
[Nature Communications]
Network models of primary melanoma microenvironments identify key melanoma regulators underlying prognosis | Nature Communications. (n.d.). Retrieved March 1, 2021, from https://www.nature.com/articles/s41467-021-21457-0 Cite
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MediWound Launches Clinical Development Program for Treatment of Non-Melanoma Skin Cancer

MediWound Ltd. announced the initiation of a new clinical development program to evaluate its drug product candidate MWPC005 in patients with non-melanoma skin cancer.
[MediWound Ltd.]
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5-Fluorouracil Efficacy Requires Anti-tumor Immunity Triggered by Cancer-Cell-Intrinsic STING

Through modeling 5‐FU response of murine colon and melanoma tumors, the authors report that effective reduction of tumor burden by 5‐FU was dependent on anti‐tumor immunity triggered by the activation of cancer‐cell‐intrinsic STING.
[EMBO Journal]
Tian, J., Zhang, D., Kurbatov, V., Wang, Q., Wang, Y., Fang, D., Wu, L., Bosenberg, M., Muzumdar, M. D., Khan, S., Lu, Q., Yan, Q., & Lu, J. (2021). 5-Fluorouracil efficacy requires anti-tumor immunity triggered by cancer-cell-intrinsic STING. The EMBO Journal, n/a(n/a), e106065. https://doi.org/10.15252/embj.2020106065 Cite
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Dutch Consortium Investigates Biomarker to Identify Early-Stage Melanoma at High-Risk of Recurrence

SkylineDx announced a research collaboration with an academic hospital and a Dutch cancer registry to investigate patients with early-stage melanoma at high risk of disease-related fatality.
[SkylineDx, Inc.]
Cohen, I., Bar, C., Liu, H., Valdes, V. J., Zhao, D., Galbo, P. M., Silva, J. M., Koseki, H., Zheng, D., & Ezhkova, E. (2021). Polycomb complexes redundantly maintain epidermal stem cell identity during development. Genes & Development. https://doi.org/10.1101/gad.345363.120 Cite
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Epitope Spreading toward Wild-Type Melanocyte-Lineage Antigens Rescues Suboptimal Immune Checkpoint Blockade Responses

Scientists report that patients with low melanoma neoantigen burdens who responded to ICI had tumors with higher expression of pigmentation-related genes.
[Science Translational Medicine]
Lo, J. A., Kawakubo, M., Juneja, V. R., Su, M. Y., Erlich, T. H., LaFleur, M. W., Kemeny, L. V., Rashid, M., Malehmir, M., Rabi, S. A., Raghavan, R., Allouche, J., Kasumova, G., Frederick, D. T., Pauken, K. E., Weng, Q. Y., Silva, M. P. da, Xu, Y., Sande, A. A. J. van der, … Fisher, D. E. (2021). Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses. Science Translational Medicine, 13(581). https://doi.org/10.1126/scitranslmed.abd8636 Cite
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