Drug development targeting the most frequently mutation G12D of KRAS has great significance. As an attractive immunotherapy, cancer vaccines can overcome binding difficulties of small molecules; however, the weak immunogenicity and production difficulties of reported KRAS mutation vaccines limit their clinical application. To improve antigen-specific immune responses and Anti-Tumor effects on tumors expressing KRAS G12D mutation, we designed recombinant proteins containing KRAS peptide (amino acids 5-21) with G12D (called SP) in two forms: DTT-SP 4 and DTSP. DTT-SP 4 was constructed by fusing four copies of SP to the C-terminal of the translocation domain of diphtheria toxin (DTT), and DTSP was constructed by grafting SP onto DTT. The two vaccines in combination with aluminum hydroxide (Alum) and cytosine phosphoguanine (CpG) successfully induced conspicuous SP-specific humoral and cellular immune responses, and displayed prominent protective and therapeutic Anti-Tumor effects in mouse CT26 tumor models. Surprisingly, the DTSP-treated group displayed better Anti-Tumor effects in vivo compared with the DTT-SP 4-treated and control groups. Moreover, 87.5 and 50% of DTSP-treated mice in the preventive and therapeutic models were tumor free, respectively. Notably, in the DTSP-treated group, the interferon-γ (IFN-γ) expression of T cells in vitro and the T-helper 1 (Th1)-related cytokine expression in tumor tissues indicated that the activated Th1 immune response may be involved in Anti-Tumor activity. Furthermore, DTSP treatment remarkably altered the subpopulation of T cells in splenocytes and tumor-infiltrating lymphocytes. The percentage of effector CD8 + T cells increased, whereas that of immunosuppressive CD4 + Foxp3 + T cells remained reduced in the DTSP group. Dramatic tumor-inhibitory effects of DTSP, which is easily prepared, make it a more attractive strategy against KRAS G12D tumors.
Background: Lung adenocarcinoma (LUAD) shows intratumoral heterogeneity, a highly complex phenomenon that known to be a challenge during cancer therapy. Considering the key role of monocytic myeloid-derived suppressor cells (M-MDSCs) in the tumor microenvironment (TME), we aimed to build a prognostic risk model using M-MDSCs-related genes.Methods: Monocytic myeloid-derived suppressor cells-related genes were extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Utilized univariate survival analysis and random forest algorithm to screen candidate genes. A least absolute shrinkage and selection operator (LASSO) Cox regression analysis was selected to build the risk model. Patients were scored and classified into high- and low-risk groups based on the median risk scores. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis along with R packages “estimate” and “ssGSEA” were performed to reveal the mechanism of risk difference. Prognostic biomarkers and tumor mutation burden (TMB) were combined to predict the prognosis. Nomogram was carried out to predict the survival probability of patients in 1, 3, and 5 years.Results: 8 genes (VPREB3, TPBG, LRFN4, CD83, GIMAP6, PRMT8, WASF1, and F12) were identified as prognostic biomarkers. The GEO validation dataset demonstrated the risk model had good generalization effect. Significantly enrichment level of cell cycle-related pathway and lower content of CD8+ T cells infiltration in the high-risk group when compared to low-risk group. Morever, The patients were from the intersection of high-TMB and low-risk groups showed the best prognosis. The nomogram demonstrated good consistency with practical outcomes in predicting the survival rate over 1, 3, and 5 years.Conclusion: The risk model demonstrate good prognostic predictive ability. The patients from the intersection of low-risk and high-TMB groups are not only more sensitive response to but also more likely to benefit from immune-checkpoint-inhibitors (ICIs) treatment.
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