المؤلفون: In, Gino K., Ribeiro, Jennifer R., Yin, Jun, Xiu, Joanne, Bustos, Matias A., Ito, Fumito, Chow, Frances, Zada, Gabriel, Hwang, Lindsay, Salama, April K. S., Park, Soo J., Moser, Justin C., Darabi, Sourat, Domingo-Musibay, Evidio, Ascierto, Maria L., Margolin, Kim, Lutzky, Jose, Gibney, Geoffrey T., Atkins, Michael B., Izar, Benjamin

المصدر: NPJ Precision Oncology; 11/14/2023, Vol. 7 Issue 1, p1-10, 10p

مصطلحات موضوعية: TUMOR microenvironment, KILLER cells, MELANOMA, OXIDATIVE phosphorylation, IMMUNE checkpoint proteins

مستخلص: Melanoma brain metastases (MBM) are clinically challenging to treat and exhibit variable responses to immune checkpoint therapies. Prior research suggests that MBM exhibit poor tumor immune responses and are enriched in oxidative phosphorylation. Here, we report results from a multi-omic analysis of a large, real-world melanoma cohort. MBM exhibited lower interferon-gamma (IFNγ) scores and T cell-inflamed scores compared to primary cutaneous melanoma (PCM) or extracranial metastases (ECM), which was independent of tumor mutational burden. Among MBM, there were fewer computationally inferred immune cell infiltrates, which correlated with lower TNF and IL12B mRNA levels. Ingenuity pathway analysis (IPA) revealed suppression of inflammatory responses and dendritic cell maturation pathways. MBM also demonstrated a higher frequency of pathogenic PTEN mutations and angiogenic signaling. Oxidative phosphorylation (OXPHOS) was enriched in MBM and negatively correlated with NK cell and B cell-associated transcriptomic signatures. Modulating metabolic or angiogenic pathways in MBM may improve responses to immunotherapy in this difficult-to-treat patient subset. [ABSTRACT FROM AUTHOR]

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المؤلفون: Carretero Coca, Rafael, Wang, Ena, Rodríguez, Ana I., Reinboth, Jennifer, Ascierto, María L., Engle, Alyson M., Liu, Hui, Camacho, Francisco M., Marincola, Francesco M., Garrido Torres-Puchol, Federico, Cabrera Castillo, María Teresa

مصطلحات موضوعية: Melanoma, Metastasis, Immunotherapy, Rejection, HLA, IRF-1

الوصف: We present the results of a comparative gene expression analysis of 15 metastases (10 regressing and 5 progressing) obtained from 2 melanoma patients with mixed response following different forms of immunotherapy. Whole genome transcriptional analysis clearly indicate that regression of melanoma metastases is due to an acute immune rejection mediated by the upregulation of genes involved in antigen presentation and interferon mediated response (STAT-1/IRF-1) in all the regressing metastases from both patients. In contrast, progressing metastases showed low transcription levels of genes involved in these pathways. Histological analysis showed T cells and HLA-DR positive infiltrating cells in the regressing but not in the progressing metastases. Quantitative expression analysis of HLA-A,B and C genes on microdisected tumoral regions indicate higher HLA expression in regressing than in progressing metastases. The molecular signature obtained in melanoma rejection appeared to be similar to that observed in other forms of immune-mediated tissue-specific rejection such as allograft, pathogen clearance, graft versus host or autoimmune disease, supporting the immunological constant of rejection. We favor the idea that the major factor determining the success or failure of immunotherapy is the nature of HLA Class I alterations in tumor cells and not the type of immunotherapy used. If the molecular alteration is reversible by the immunotherapy, the HLA expression will be upregulated and the lesion will be recognized and rejected. In contrast, if the defect is structural the MHC Class I expression will remain unchanged and the lesion will progress. ; Fondo de Investigaciones Sanitarias (FIS). Grant Numbers: CP03/0111, PI 08/1265. Proyecto de investigacion MEC I + D. Grant Numbers: SAF 2007-63262, SAF 2010-20273. Red Genomica del Cancer. Grant Number: RETIC RD 06/020. Plan Andaluz de Investigacion. Grant Numbers: CTS 143, CTS-695. Proyectos de Excelencia. Grant Numbers: CTS-03952, CVI-04740. Integrated European Cancer ...

وصف الملف: application/pdf

العلاقة: Carretero, R.; et al. Regression of melanoma metastases after immunotherapy is associated with activation of antigen presentation and interferon-mediated rejection genes. International Journal of Cancer, 131(2): 387-395 (2012). [The definitive version is available at www3.interscience.wiley.com]. [http://hdl.handle.net/10481/29170Test]; PMCID: PMC3504975; http://hdl.handle.net/10481/29170Test

الإتاحة: https://doi.org/10.1002/ijc.26471Test
http://hdl.handle.net/10481/29170Test