We previously reported that antitumor B cells directly kill tumor cells via the Fas/FasL pathway and are regulated by IL-10. In this study, we defined additional mechanisms involved in B cell antitumor immunity. Administration of IL-2 significantly augmented the therapeutic efficacy of adoptively transferred tumor-draining lymph node (TDLN) B cells which express IL- 2R. Culture supernatant of purified B splenocytes harvested from the mice that received adoptive transfer of 4T1 TDLN B cells plus IL-2 administration produced larger amounts of IgG which bound to 4T1, resulting in 4T1 lysis. Furthermore, we detected CXCR4 expression on 4T1 TDLN B cells, and 4T1 tumor cells produced its ligand CXCL12. Transwell experiments demonstrated the chemoattraction of CXCR4-expressing 4T1 TDLN B cells towards CXCL12- producing 4T1 cells. Blockade of CXCR4 using a CXCR4-specific inhibitor, AMD3100, significantly reduced the killing of 4T1 tumor cells by 4T1 TDLN B cells. Blockade of FasL and CXCR4 concurrently inhibited B cell-mediated direct killing of tumor cells in an additive manner, indicating that both Fas/FasL and CXCL12/CXCR4 pathways are involved in the direct killing of 4T1 cells by 4T1 TDLN B cells. TDLN B cells produced perforin. Additional transwell experiments showed that effector B cells could directly kill tumor cells in cell-cell contact via the Fas/FasL and CXCR4/CXCL12 pathways as well as perforin, while without cell contact, perforin secreted by B cells led to tumor cell cytotoxicity. These findings underscore the diversity of function by which B cells can play an important role in the host immune response to tumor.
Mucin1 (MUC1) proteins represent a family of high molecular weight trans-membrane glycoproteins that protect epithelial cells and mediate signal transduction by communication with extracellular stimuli. On the other hand, MUC1 has been observed to be overexpressed and glycosylated in adenocarcinoma, making it an ideal molecular target for cancer treatment. MUC1 based antibody and specific chimeric antigen receptors (CARs) modified T/NK cells exhibit strong antibody-dependent or direct-cell cytotoxicity to MUC1 positive tumor cells. However, treatment failure with MUC1-targeted therapy was usually caused by tumor microenvironment (TME)-driven immune suppression. PD-L1 has been identified as a negative checkpoint molecule that promotes immune evasion of tumor cells. The interaction of PD-1 and PD-L1 inhibits the function of tumor-infiltrating lymphocytes (TILs) or infused T/NK cells while activating the negative immune-regulatory cells in TME, such as regulatory T-cells and MDSCs. To overcome these barriers, we engineered clinically applicable NK-92 cells by lentiviral gene transfer to express chimeric antigen receptors comprising an anti-MUC1 scFv antibody fusion protein with CD28-CD137 as a signaling moiety and truncated PD-1 peptide. NK92 cells expressing anti-MUC1 CAR specifically and efficiently lysed MUC1 positive tumor cells in vitro and in vivo. The safety of NK-92 cell administration has been demonstrated by numerous phase I clinical trials. In our study, 13 patients with different kinds of tumors (lung cancer, pancreatic cancer, colon cancer and ovarian cancer) with positive PD-L1 and MUC-1 expression were enrolled. CAR-NK cells were infused (1×109 cells/time) into these patients. Of 13 patients, 3 patients were withdrawn, 9 patients (69.2%) showed stable disease and 1 patient showed progressive disease. The cytokine level and hematologic changes were monitored to evaluate the safety. Severe cytokine storm and/or bone marrow suppression were not observed. From this phase I clinical trial we found that CAR-NK therapy has a broad prospect of application as a new cellular immunotherapy due to its stable clinical efficacy, mild side effects and ease of preparation. Citation Format: Qiao Li, Yi Wang, Ming Lin, Leiming Xia, Yangyi Bao, Xiang Sun, Lin Yang. Phase I clinical trial with PD-1/MUC1 CAR-pNK92 immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A014.
BackgroundThe main purpose of this study was to explore the antitumor effect and mechanisms of ACAT1 inhibitor combined with CSCs-DC vaccine.Material/MethodsWe isolated HNSCC CSCs and gained CSCs antigens, then used CSCs antigens to load dendritic cells (DC) and generated a CSCs-DC vaccine. We treated mice after surgical excision of established SCC7 tumors with CSCs-DC vaccine and/or ACAT1 inhibitor, and recorded local tumor relapse and host survival. T cells and B cells were harvested from mice treated with CSCs-DC vaccine and/or ACAT1 inhibitor. We tested antibody production and the death rate of CSCs killed by T cells.ResultsThe tumors in the combined treatment group were smaller than in all other groups (P<0.01). The average survival time of the combined treatment group was 82 days and was the longest of all groups. Analysis of IgG levels secreted by B cell and CTL activity in spleens of mice found that results of the combined treatment group were the highest, and the results of the CSCs-DC group were lower than in the combined treatment group. The ACAT1 inhibitor group results were lower than in the CSCs-DC group and the combined treatment group results, but higher than in the PBS group, and the difference was statistically significant.ConclusionsACAT1 inhibitor enhanced the therapeutic effect of CSCs-DC vaccine in the treatment of the mouse HNSCC postoperative recurrence model. ACAT1 may play an important role in cancer immunotherapy.
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