Inhibition Of Superantigenic Staphylococcus Aureus Enterotoxin SEC2-Modifying Protein 2M-118 On Colorectal Tumorigenesis In Mice

Colorectal cancer(CRC)is the fourth most deadly cancer in the world.In addition to an aging population and a high-sugar,high-protein diet in high-income countries,adverse risk factors such as obesity,lack of physical activity,and smoking increase the risk of CRC.Among the various therapeutic approaches for CRC,immunotherapy and adjuvant systemic therapy for tumors have developed particularly rapidly.Superantigen Staphylococcus aureus enterotoxin SEC2 and its multiple mutants have been shown to stimulate the immune system with excellent efficiency,activate lymphocytes,promote their proliferation,and have a high potential for immunotherapy of tumors.But SEC2 is more strongly emetogenic,and pyrotoxic.2M-118 is a novel SEC2 mutant that has been developed in recent years,aiming to enhance its superantigenicity and attenuate its toxicity through the substitution of essential amino acid residues.In the present study,we first examined the toxicogenic immunogenicity of 2M-118 by in-vitro and in-vivo assays and then investigated the pharmacodynamic effects and specific mechanisms of 2M-118 on mouse CRC using an AOM/DSS-induced mouse CRC model.In the present study,we first examined the toxicogenic immunogenicity of 2M-118 by in vitro and mouse in vivo assays.We then investigated the pharmacodynamic effects and specific mechanisms of 2M-118 on mouse colon cancer using an AOM/DSS-induced mouse colon cancer model.In the toxicity and immunogenicity assays,we observed that 2M-118 did not cause vomiting or elevated body temperature in mice;2M-118 upregulated cytokine expression of IFN-γ,TNF-α,and IL-2 in mouse spleen tissues and promoted the proliferation of mouse spleenderived lymphocytes,and mice could produce neutralizing antibodies that rapidly cleared 2M-118 blood concentrations.During the establishment of the cancer model,mice were monitored daily for changes in body weight,and at the end of modeling,the colon was obtained,photographed,and subjected to H.E.staining for pathological tissue examination.Colon unit weight was counted to determine the pharmacodynamic effects of 2M-118 on mice with CRC.The results showed that 2M-118 was able to reduce colon unit weight,and the number and size of colon tumors in the treated group were significantly reduced.The malignancy of colon tumors in the treated group was improved from the pathological point of view,indicating that 2M-118 could substantially improve the AOM-DSS-induced CRC in mice.Therefore,we also detected and verified the gene expression level of colon tissue and the expression of cytokines in colon tissue and spleen tissue of mice with CRC by transcriptomic monitoring analysis,ELISA,and RT-q PCR.The results showed that 2M-118 could upregulate the expression of IFN-γ,TNF-α,B2 m,IFN-γ,IL-2,IL-2R,H2-D1,H2-K1,TAP1,TAP2,T-Bet,Cd8 a in colon tissues of mice with CRC,and upregulate IFN-γ,TNF-α,and IL-2 expression in spleen tissues,which suggested 2M-118 could promote biological processes that enhance immune antigen presentation,innate immunity,adaptive immunity,and T cell-related cytotoxicity to enhance the immune system to alleviate tumors.In summary,2M-118 may activate lymphocytes,promote lymphocyte proliferation and enhance the lymphatic system’s ability to kill tumors by upregulating genes related to the biological processes of immune antigen presentation,intrinsic immunity,adaptive immunity,and T-cell-associated cytotoxicity.