Objectives Patients with PD-L1-negative non-small cell lung cancer (NSCLC) often exhibit inherent PD-1 inhibitor resistance, leading to poor monotherapy efficacy and unfavorable clinical outcomes. Notably, no effective stratification biomarkers are currently available to overcome this resistance. Thus, this study aimed to reverse PD-1 inhibitor resistance in PD-L1-negative NSCLC by identifying novel predictive biomarkers and developing effective targeted immunotherapeutic regimens. Methods Pleural effusion-derived organoids (PEOs) were established and validated from driver gene wild-type, PD-L1-negative NSCLC patients. Four treatment groups were set: control, anti-PD-1 monotherapy (Toripalimab), anti-CD73 monotherapy (Uliledlimab), and anti-PD-1 + anti-CD73 combination (Toripalimab + Uliledlimab). ATP assay was used to detect tumor cell viability. Spearman’s rank correlation analysis was applied to evaluate the association between CD73 expression and tumor inhibition rates. Flow cytometry was employed to measure T cell activation markers. Enzyme-linked Immunospot assay was used to detect IFN-γ and TNF-α secretion. Results PEO models recapitulated the biological features of primary pleural effusion. Toripalimab monotherapy showed no antitumor efficacy in PD-L1-negative subgroup regardless of CD73 expression levels, whereas Toripalimab + Uliledlimab combination significantly reversed PD-1 inhibitor resistance in CD73-high PD-L1-negative NSCLC patients. Furthermore, a significant positive correlation was observed between CD73 expression levels and tumor inhibition rates. Conclusion This study validates CD73 as a potential predictive biomarker for stratifying PD-L1-negative NSCLC patients and establishes anti-PD-1+ anti-CD73 combination regimen that effectively reverses PD-1 inhibitor resistance in CD73-high PD-L1-negative NSCLC patients.
Objective: To summarise the clinical and familial characteristics of two patients with Epstein–Barr virus (EBV)-associated T/NK-cell lymphoproliferative diseases carrying heterozygous IL10RA variants and to explore their potential genetic significance. Methods: We retrospectively analysed the clinical courses, pathological findings, flow cytometry results, EBV detection in sorted cell populations, genetic testing results, and familial segregation data of the two patients, supplemented by a review of the relevant literature. Results: Patient 1 was a 34-year-old man who presented with fever, gastrointestinal bleeding, and multiple colonic ulcers. EBV was predominantly detected in NK cells, followed by persistent expansion of abnormal NK cells, bone marrow involvement, and progression to NK/T-cell lymphoma complicated by haemophagocytic lymphohistiocytosis. Genetic testing identified a heterozygous IL10RA c.85 C>G (p.Pro29Ala) variant, which was also detected in his mother and one sister. Patient 2 was a 32-year-old man with long-standing hepatosplenomegaly, cytopenia, and abnormal liver function. Histopathological examination and EBV testing of sorted cell populations indicated predominant T-cell involvement, with concurrent NK-cell involvement. He carried a heterozygous IL10RA c.301 C>T (p.Arg101Trp) variant, which was also identified in his mother. The p.Pro29Ala variant is currently classified as a variant of uncertain significance, whereas p.Arg101Trp is a known pathogenic allele associated with autosomal recessive IL10RA -related disease. Conclusion: Both adult patients with EBV-associated T/NK-cell lymphoproliferative diseases carried a single heterozygous missense variant in IL10RA . However, the same variants were also present in family members without a similar phenotype, and the available evidence is insufficient to establish a direct causal relationship. IL10RA genetic variation warrants further investigation as a potential host susceptibility factor for EBV-associated T/NK-cell diseases.
Objective To summarise the clinical and familial characteristics of two patients with Epstein–Barr virus (EBV)-associated T/NK-cell lymphoproliferative diseases carrying heterozygous IL10RA variants and to explore their potential genetic significance. Methods We retrospectively analysed the clinical courses, pathological findings, flow cytometry results, EBV detection in sorted cell populations, genetic testing results, and familial segregation data of the two patients, supplemented by a review of the relevant literature. Results Patient 1 was a 34-year-old man who presented with fever, gastrointestinal bleeding, and multiple colonic ulcers. EBV was predominantly detected in NK cells, followed by persistent expansion of abnormal NK cells, bone marrow involvement, and progression to NK/T-cell lymphoma complicated by haemophagocytic lymphohistiocytosis. Genetic testing identified a heterozygous IL10RA c.85 C>G (p.Pro29Ala) variant, which was also detected in his mother and one sister. Patient 2 was a 32-year-old man with long-standing hepatosplenomegaly, cytopenia, and abnormal liver function. Histopathological examination and EBV testing of sorted cell populations indicated predominant T-cell involvement, with concurrent NK-cell involvement. He carried a heterozygous IL10RA c.301 C>T (p.Arg101Trp) variant, which was also identified in his mother. The p.Pro29Ala variant is currently classified as a variant of uncertain significance, whereas p.Arg101Trp is a known pathogenic allele associated with autosomal recessive IL10RA-related disease. Conclusion Both adult patients with EBV-associated T/NK-cell lymphoproliferative diseases carried a single heterozygous missense variant in IL10RA. However, the same variants were also present in family members without a similar phenotype, and the available evidence is insufficient to establish a direct causal relationship. IL10RA genetic variation warrants further investigation as a potential host susceptibility factor for EBV-associated T/NK-cell diseases.
Glucose-6-phosphate isomerase (GPI) is a key metabolic enzyme implicated in tumorigenesis, yet its pan-cancer role and clinical significance remain incompletely understood. This study aimed to systematically characterize GPI expression, genetic alterations, clinical relevance, and biological functions across cancers, and validate its pro-oncogenic effects.We employed bioinformatics tools (GEPIA2, SangerBox 3.0, cBioPortal, TIMER 2.0, etc.) to analyze GPI expression, genetic alterations, and clinical relevance across multiple cancer types. In vitro experiments were conducted to validate its pro-oncogenic effects in LGG cells.Bioinformatics analyses showed that GPI was upregulated in 29 cancers and downregulated in 3 cancers. High GPI expression was associated with advanced stage, metastasis and poor prognosis. Genetic alterations positively regulated GPI expression, which was linked to cancer stemness, RNA modification, metabolic pathways and tumor immune microenvironment, and could predict chemotherapy response. In vitro experiments confirmed that GPI overexpression promoted LGG cell proliferation, colony formation and invasion, while knockdown inhibited these phenotypes. The correlation between DNA repair and GPI expression is interconnected through metabolic and genetic instability pathways, requiring further investigation.GPI acts as a pan-cancer pro-oncogenic factor and a promising diagnostic, prognostic, and therapeutic biomarker. Further research on its molecular mechanisms, particularly with DNA repair, will inform novel cancer treatment strategies.
