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1.
Nat Immunol ; 25(6): 1020-1032, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38831106

RESUMEN

The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM (TNFRSF14) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA-HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier.


Asunto(s)
Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Receptores Inmunológicos , Miembro 14 de Receptores del Factor de Necrosis Tumoral , Microambiente Tumoral , Animales , Humanos , Inmunoterapia Adoptiva/métodos , Miembro 14 de Receptores del Factor de Necrosis Tumoral/metabolismo , Miembro 14 de Receptores del Factor de Necrosis Tumoral/inmunología , Miembro 14 de Receptores del Factor de Necrosis Tumoral/genética , Ratones , Microambiente Tumoral/inmunología , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/genética , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Linfocitos T Reguladores/inmunología , Transducción de Señal , Línea Celular Tumoral , Neoplasias/inmunología , Neoplasias/terapia , Ratones Noqueados
2.
Am J Physiol Lung Cell Mol Physiol ; 326(5): L646-L650, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38529551

RESUMEN

Novel screening techniques for early detection of lung cancer are urgently needed. Profiling circulating tumor cell-free DNA (ctDNA) has emerged as a promising tool for biopsy-free tumor genotyping. However, both the scarcity and short half-life of ctDNA substantially limit the sensitivity and clinical utility of ctDNA detection methodologies. Our discovery that red blood cells (RBCs) sequester mitochondrial DNA opens a new avenue for detecting circulating nucleic acids, as RBCs represent an unrecognized reservoir of circulating nucleic acid. Here, we show that RBCs acquire tumor DNA following coculture with lung cancer cell lines harboring Kirsten rat sarcoma viral oncogene homolog (KRAS) and epidermal growth factor receptor (EGFR) mutations. RBC-bound tumor DNA is detectable in patients with early-stage non-small cell lung cancer (NSCLC) but not in healthy controls by qPCR. Our results collectively uncover a previously unrecognized yet easily accessible reservoir of tumor DNA, offering a promising foundation for future RBC-based tumor diagnostics.NEW & NOTEWORTHY We present a novel method for lung cancer detection by revealing RBCs as a reservoir for tumor DNA, overcoming the limitations of current circulating tumor ctDNA methodologies. By demonstrating that RBCs can capture tumor DNA, including critical mutations found in lung cancer, we provide a promising, biopsy-free avenue for early cancer diagnostics. This discovery opens up exciting possibilities for developing RBC-based diagnostic tools, significantly enhancing the sensitivity and clinical utility of noninvasive cancer detection.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Eritrocitos , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico , Eritrocitos/metabolismo , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Mutación , Línea Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , ADN Mitocondrial/genética , ADN Mitocondrial/sangre , Proteínas Proto-Oncogénicas p21(ras)/genética , Masculino , Femenino , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , ADN de Neoplasias/sangre , ADN de Neoplasias/genética
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