Single-cell transcriptomic analysis uncovers intratumoral heterogeneity and drug-tolerant persister in ALK-rearranged lung adenocarcinoma

Dear Editor,Non-small cell lung carcinoma(NSCLC)accounts for more than 85%of all lung cancers[1].Lung adenocarcinomas(ADCs)arising from never-smokers have been frequently found to be associated with oncogenic driver mutations,including anaplastic lymphoma kinase(ALK)rearrangement.Echinoderm microtubule-associated protein-like 4(EML4)is the most common fusion partner of the ALK gene[2].Tyrosine kinase inhibitors(TKIs)are currently the first-line treatment for advanced EML4-ALKrearranged lung ADC.

Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer

Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy.Due to their HLA-independent mode of action,allogeneic Vγ9Vδ2 T cells can be considered for clinical application.To apply allogeneic Vγ9Vδ2 T cells in adoptive immunotherapy,the methodology used to obtain adequate cell numbers with optimal effector function in vitro needs to be optimized,and clinical safety and efficacy also need to be proven.Therefore,we developed a novel formula to improve the expansion of peripheralγδT cells from healthy donors.Then,we used a humanized mouse model to validate the therapeutic efficacy of expandedγδT cells in vivo;furthermore,the expandedγδT cells were adoptively transferred into late-stage liver and lung cancer patients.We found that the expanded cells possessed significantly improved immune effector functions,including proliferation,differentiation,and cancer cell killing,both in vitro and in the humanized mouse model.Furthermore,a phase I clinical trial in 132 late-stage cancer patients with a total of 414 cell infusions unequivocally validated the clinical safety of allogeneic Vγ9Vδ2 T cells.Among these 132 patients,8 liver cancer patients and 10 lung cancer patients who received≥5 cell infusions showed greatly prolonged survival,which preliminarily verified the efficacy of allogeneic Vγ9Vδ2 T-cell therapy.Our clinical studies underscore the safety and efficacy of allogeneic Vγ9Vδ2 T-cell immunotherapy,which will inspire further clinical investigations and eventually benefit cancer patients.