Anti-Human CD4 monoclonal antibody

Objectives: The efficacy of anti- programmed cell death 1 (PD-1)/PD-1 ligand (PD-L1) immune checkpoint inhibitors remains controversial in patients with KRAS mutation. In addition, whether and how KRAS gene and its mutant subtypes might influence immunity has not been clarified yet. Here we examine some important biomarkers for the efficacy of immunotherapy in specific KRAS subtypes. Materials and Methods: We conducted a bioinformatics analysis on somatic mutations data, transcriptome sequencing data and proteomic data from The Cancer Genome Atlas (TCGA) database. CIBERSORT was used to provide an estimation of the abundances of immune cells using gene expression data. Results: From a cohort of 567 patients with lung adenocarcinoma (LUAD) based on TCGA, the overall mutation rate of KRAS was 26.29 %, including KRAS/TP53 co-mutation rate of 9.7 %. We observed increased Tumor mutation burden (TMB) in KRAS mutant group compared with wild type, while no difference in PD-L1 expression and immune cell infiltration. More importantly, TP53 and KRAS/TP53 co-mutation group not only significantly increased tumor mutation burden, but also had higher PD-L1 protein level and immune cell infiltration. We further focused on influence of KRAS mutant subtype on immune biomarker. The most prevalent mutant subtype of KRAS in lung adenocarcinoma was G12C(9.88 %,56/567), followed by G12 V(5.82 %,33/567), G12D(3.00 %,17/567), G12A(3.00 %,17/567), respectively. Among them, G12D mutation appeared to be a special mutant subtype with an obviously lower TMB. This low mutation load was more significant when co-mutation with TP53. Besides, our results also revealed significantly decreased expressions of PD-L1 protein level and immune cell infiltration (activated CD4 memory T cell, helper T cell, M1 macrophage and NK cell) in KRAS G12D/TP53 mutant group. Conclusion: KRAS G12D/TP53 co-mutation drives immune suppression and might be a negative predictive biomarker for anti-PD-1/PD-L1 immune checkpoint inhibitors in patients with lung adenocarcinoma.

Patients with rheumatoid arthritis (RA) are more susceptible to infections, which elevate the levels of relative cytokines. However, the ability of the cytokines levels to predicate bacterial infections in RA patients remains unclear. Here, we assessed the ability of the combination of serum cytokine levels and blood parameters to diagnose bacterial infections in RA patients. We measured the levels of a panel of serum cytokine and blood parameters in 168 RA patients and 81 healthy individuals. RA patients were divided into the bacterial infection (INFE) group (n = 76) and RA flare without INFE group (n = 92). Bacterial infection was confirmed by microbial culture, imaging, antibiotic response, and typical clinical symptoms. The discriminative ability of the combination of the cytokine levels and inflammatory parameters was assessed using the receiver-operating characteristic (ROC) curves analysis and a novel bioscore system. The levels of interleukin (IL)-6 (p = 0.006), IL10 (p = 0.019), interferon (IFN)-gamma (p = 0.033), CRP (p < 0.001), and ESR (p < 0.001) were higher in patients of the INFE group than in patients with RA flare, and the absolute numbers of CD19(+) B cells (p < 0.001) and CD4(+) T cells (p = 0.009) were lower. For discriminating bacterial infection, the combination of IL-6, IL-10, IFN-gamma, ESR, CRP, CD19(+) B cells, and CD4(+) T cells, provided an area under the curve (AUC) of 0.827 [(95% confidence interval (CI): 0.760-0.881)], which was profoundly larger than that of IL-6, IL-10, IFN-gamma, ESR, CRP, CD19(+) B cells, or CD4(+) T cells alone. In addition, we also developed a bioscore system based on the combination of these seven biomarkers. Seventeen (100%) patients with a bioscore of 0 were non-infected, while seven (100%) patients with a score of 7 had bacterial infections. The bioscore based on the combination of ESR, CRP, IL-6, IL-10, IFN-gamma, CD19(+) B cells and CD4(+) T cells may be a promising and robust tool to diagnose bacterial infections in RA patients.