Mesothelin-targeted CAR-NK Cells Derived From Induced Pluripotent Stem Cells Have a High Efficacy in Killing Triple-negative Breast Cancer Cells as Shown in Several Preclinical Models.

The emergence of immunotherapy has introduced a promising, novel approach to cancer treatment. While multiple chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable clinical efficacy against leukemia, their effect on solid tumors has been limited. One potential option for treating solid tumors is the engineering of natural killer (NK) cells with CARs. Mesothelin (MSLN), a tumor differentiation antigen, is expressed on triple-negative breast cancer (TNBC) cells, making it a potential target for CAR-NK therapy in the treatment of TNBC. We first constructed induced pluripotent stem cells with stable anti-MSLN-CAR expression and subsequently differentiated these cells into mesothelin-targeted CAR-NK (MSLN-NK) cells. We then assessed the effects of MSLN-NK cells on TNBC cells both in vitro (using the MDA-MB-231 cell line), in vivo (in a CDX mouse model), and ex vivo (using patient-specific primary cells and patient-specific organoids), in which MSLN surface expression was confirmed. Our CDX study results indicated that MSLN-NK cells effectively killed MDA-MB-231 (MD231) cells in vitro, reduced tumor growth in the CDX mouse model of TNBC, and lysed patient-specific primary cells and patient-specific organoids derived from the tumor samples of TNBC patients. Our data demonstrated that MSLN-NK cells had high efficacy on killing TNBC cells in in vitro, in vivo, and ex vivo. Therefore, MSLN-NK could be a promising treatment option for TNBC patients.

Protective effect of glutathione S-transferase-fused mutant staphylococcal enterotoxin C against Staphylococcus aureus-induced bovine mastitis.

Recent studies have demonstrated that immunization with nontoxic mutant staphylococcal enterotoxin C (mSEC) provides protection against Staphylococcus aureus infection in mouse models. In the present study, we investigated whether vaccination with a glutathione S-transferase-fused SEC (GST-mSEC) can protect against S. aureus-induced bovine mastitis. Cows were immunized with the GST-mSEC plus alum adjuvant and then challenged with viable S. aureus by an intramammary route. The results showed that immunization with GST-mSEC-induced production of SEC-specific antibodies in sera and the high titers of antibodies could persist for over 12 weeks. Importantly, immunization with GST-mSEC also induced production of SEC-specific antibodies in milk. The somatic cell counts in the milk from S. aureus challenged quarters of vaccinated lactating cows were significantly lower than those of the non-vaccinated control animals. Furthermore, the sera from GST-mSEC-immunized cows significantly inhibited interferon-gamma and tumor necrosis factor-alpha production from mouse spleen cells induced by wild-type SEC. These results suggest that vaccination with GST-mSEC provides protection against S. aureus-induced bovine mastitis and that the protection might be mediated by SEC-neutralizing antibodies.

Immunization with glutathione S-transferase and mutant toxic shock syndrome toxin 1 fusion protein protects against Staphylococcus aureus infection.

To investigate whether immunization with glutathione S-transferase (GST) and mutant toxic shock syndrome toxin 1 (mTSST-1) fusion protein can protect against Staphylococcus aureus infection, we purified a non-toxic mutant GST-mTSST-1 fusion protein. Mice were immunized with the GST-mTSST-1 plus alum adjuvant and then challenged with viable S. aureus. The results showed that the survival rate of GST-mTSST-1-immunized group was higher and the bacteria counts in the organs were significantly lower than those of the non-immunized mice. Immunization with GST-mTSST-1 induced strongly the production of TSST-1 specific antibodies, especially immunoglobulin G1 and immunoglobulin G2b. Furthermore, the serum samples from GST-mTSST-1-immunized mice also significantly inhibited interferon-gamma and tumor necrosis factor-alpha production from murine spleen cells by TSST-1. These results suggest that vaccination with GST-mTSST-1 provides protection against S. aureus infection and that the protection might be mediated by TSST-1-neutralizing antibody.