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1.
Cell ; 179(1): 219-235.e21, 2019 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-31522890

RESUMEN

Although clonal neo-antigen burden is associated with improved response to immune therapy, the functional basis for this remains unclear. Here we study this question in a novel controlled mouse melanoma model that enables us to explore the effects of intra-tumor heterogeneity (ITH) on tumor aggressiveness and immunity independent of tumor mutational burden. Induction of UVB-derived mutations yields highly aggressive tumors with decreased anti-tumor activity. However, single-cell-derived tumors with reduced ITH are swiftly rejected. Their rejection is accompanied by increased T cell reactivity and a less suppressive microenvironment. Using phylogenetic analyses and mixing experiments of single-cell clones, we dissect two characteristics of ITH: the number of clones forming the tumor and their clonal diversity. Our analysis of melanoma patient tumor data recapitulates our results in terms of overall survival and response to immune checkpoint therapy. These findings highlight the importance of clonal mutations in robust immune surveillance and the need to quantify patient ITH to determine the response to checkpoint blockade.


Asunto(s)
Heterogeneidad Genética/efectos de la radiación , Melanoma/genética , Melanoma/inmunología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Rayos Ultravioleta/efectos adversos , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Estudios de Cohortes , Modelos Animales de Enfermedad , Femenino , Humanos , Linfocitos Infiltrantes de Tumor , Melanoma/mortalidad , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Mutación/efectos de la radiación , Filogenia , Neoplasias Cutáneas/mortalidad , Tasa de Supervivencia , Linfocitos T/inmunología , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de la radiación
2.
Nature ; 592(7852): 138-143, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33731925

RESUMEN

A variety of species of bacteria are known to colonize human tumours1-11, proliferate within them and modulate immune function, which ultimately affects the survival of patients with cancer and their responses to treatment12-14. However, it is not known whether antigens derived from intracellular bacteria are presented by the human leukocyte antigen class I and II (HLA-I and HLA-II, respectively) molecules of tumour cells, or whether such antigens elicit a tumour-infiltrating T cell immune response. Here we used 16S rRNA gene sequencing and HLA peptidomics to identify a peptide repertoire derived from intracellular bacteria that was presented on HLA-I and HLA-II molecules in melanoma tumours. Our analysis of 17 melanoma metastases (derived from 9 patients) revealed 248 and 35 unique HLA-I and HLA-II peptides, respectively, that were derived from 41 species of bacteria. We identified recurrent bacterial peptides in tumours from different patients, as well as in different tumours from the same patient. Our study reveals that peptides derived from intracellular bacteria can be presented by tumour cells and elicit immune reactivity, and thus provides insight into a mechanism by which bacteria influence activation of the immune system and responses to therapy.


Asunto(s)
Antígenos Bacterianos/análisis , Antígenos Bacterianos/inmunología , Bacterias/inmunología , Antígenos HLA/inmunología , Melanoma/inmunología , Melanoma/microbiología , Péptidos/análisis , Péptidos/inmunología , Presentación de Antígeno , Bacterias/clasificación , Bacterias/genética , Línea Celular Tumoral , Técnicas de Cocultivo , Antígenos HLA/análisis , Humanos , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/patología , Metástasis de la Neoplasia/inmunología , Filogenia , ARN Ribosómico 16S/genética
3.
Pigment Cell Melanoma Res ; 33(2): 334-344, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31549767

RESUMEN

NRAS mutations are the most common alterations among RAS isoforms in cutaneous melanoma, with patients harboring these aggressive tumors having a poor prognosis and low survival rate. The main line of treatment for these patients is MAPK pathway-targeted therapies, such as MEK inhibitors, but, unfortunately, the response to these inhibitors is variable due to tumor resistance. Identifying genetic modifiers involved in resistance toward MEK-targeted therapy may assist in the development of new therapeutic strategies, enhancing treatment response and patient survival. Our whole-genome CRISPR-Cas9 knockout screen identified the target Kelch domain-containing F-Box protein 42 (FBXO42) as a factor involved in NRAS-mutant melanoma-acquired resistance to the MEK1/2 inhibitor trametinib. We further show that FBXO42, an E3 ubiquitin ligase, is involved in the TAK1 signaling pathway, possibly prompting an increase in active P38. In addition, we demonstrate that combining trametinib with the TAK1 inhibitor, takinib, is a far more efficient treatment than trametinib alone in NRAS-mutant melanoma cells. Our findings thus show a new pathway involved in NRAS-mutant melanoma resistance and provide new opportunities for novel therapeutic options.


Asunto(s)
Resistencia a Antineoplásicos/genética , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , GTP Fosfohidrolasas/genética , Genoma Humano , Melanoma/genética , Proteínas de la Membrana/genética , Neoplasias Cutáneas/genética , Secuencia de Bases , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Sistemas CRISPR-Cas/genética , Línea Celular Tumoral , Pruebas Genéticas , Humanos , Quinasas Quinasa Quinasa PAM/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/genética , Melanoma/tratamiento farmacológico , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Modelos Biológicos , Mutación/genética , Unión Proteica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridonas/farmacología , Piridonas/uso terapéutico , Pirimidinonas/farmacología , Pirimidinonas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico
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