RESUMO
Chimeric antigen receptor (CAR) T cells are effective against hematological cancers, but are less effective against solid tumors such as non-small cell lung cancer (NSCLC). One of the reasons is that only a few cell surface targets specific for NSCLC cells have been identified. Here, we report that CD98 heavy chain (hc) protein is overexpressed on the surface of NSCLC cells and is a potential target for CAR T cells against NSCLC. Screening of over 10,000 mAb clones raised against NSCLC cell lines showed that mAb H2A011 bound to NSCLC cells but not normal lung epithelial cells. H2A011 recognized CD98hc. Although CAR T cells derived from H2A011 could not be established presumably due to the high level of H2A011 reactivity in activated T cells, those derived from the anti-CD98hc mAb R8H283, which had been shown to lack reactivity with CD98hc glycoforms expressed on normal hematopoietic cells and some normal tissues, were successfully developed. R8H283 specifically reacted with NSCLC cells in six of 15 patients. R8H283-derived CAR T cells exerted significant anti-tumor effects in a xenograft NSCLC model in vivo. These results suggest that R8H283 CAR T cells may become a new therapeutic tool for NSCLC, although careful testing for off-tumor reactivity should be performed in the future.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Imunoterapia Adotiva , Neoplasias Pulmonares , Animais , Feminino , Humanos , Camundongos , Anticorpos Monoclonais/imunologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Cadeia Pesada da Proteína-1 Reguladora de Fusão/metabolismo , Imunoterapia Adotiva/métodos , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The regulation of estrogen activity through the formation and cleavage of sulfoconjugates of estrogens is known to be related to the progression and metastasis of estrogen-dependent breast carcinomas, but the involvement of sulfoconjugates in the steroid stimulation of endometrial functions and the progression of endometrial adenocarcinomas is not clearly understood yet. Estrogen sulfotransferase (EST) in the uterine endometria during the follicular phase was more active than during the luteal phase, but estrogen sulfate (ES) sulfatase exhibited lower activity during the follicular phase than during the luteal phase. However, ES sulfatase activities in cancerous tissues were lower than those in normal endometria and endometrial adenocarcinoma-derived cells, among which the activity was exceedingly high in Ishikawa cells, suggesting that ES sulfatase in Ishikawa cells contributes to the estrogen-dependent growth of these cells. EST activities higher than that in Ishikawa cells were found in only 3 of 24 cancerous tissues. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of the EST and ES sulfatase genes in carcinoma-derived cells demonstrated the extensive expression of both genes in Ishikawa cells. The isolated EST gene was transfected into Ishikawa cells with a mammalian expression vector to establish cell clones with enhanced EST activity, and the estrogen-dependent cell growth of the resultant cell clones was found to be abolished, due to the enhanced sulfoconjugation of estrogen. Since ES sulfatase activity in cancerous tissues was significantly lower than that in Ishikawa cells, it might be not involved in the enhancement of estrogen activity associated with the pathogenesis of endometrial adenocarcinoma tissues.