Abstract
The introduction of checkpoint inhibitors represents a major advance in cancer immunotherapy. Some studies on checkpoint inhibition demonstrate that combinatorial immunotherapies with secondary drivers of anti-tumor immunity provide beneficial effects for patients that do not show a strong endogenous immune response. CD40-activated B cells (CD40B cells) are potent antigen presenting cells by activating and expanding naïve and memory CD4+ and CD8+ and homing to the secondary lymphoid organs. In contrast to dendritic cells, the generation of highly pure CD40B cells is simple and time efficient and they can be expanded almost limitlessly from small blood samples of cancer patients. Here, we show that the vaccination with antigen-loaded CD40B cells induces a specific T-cell response in vivo comparable to that of dendritic cells. Moreover, we identify vaccination parameters, including injection route, cell dose and vaccination repetitions to optimize immunization and demonstrate that application of CD40B cells is safe in terms of toxicity in the recipient. We furthermore show that preventive immunization of tumor-bearing mice with tumor antigen-pulsed CD40B cells induces a protective anti-tumor immunity against B16.F10 melanomas and E.G7 lymphomas leading to reduced tumor growth. These results and our straightforward method of CD40B-cell generation underline the potential of CD40B cells for cancer immunotherapy.
Highlights
A major advance in cancer immunotherapy has been the development of checkpoint inhibitors, which show clinical efficacy in a variety of advanced malignancies [1,2,3,4]
Our results presented in this study support the potential of CD40B cells for cancer immunotherapy and underline the importance of the optimal vaccination strategy for cellular immunotherapy
Lee et al [45] and Guo et al [46] used monoclonal anti-CD40 antibodies to activate their B cells, which did not result in the same elevated expression levels of costimulatory and MHC molecules that we observed in our study by using CD40 ligand (CD40L)-expressing feeder cells for the activation of B cells
Summary
A major advance in cancer immunotherapy has been the development of checkpoint inhibitors, which show clinical efficacy in a variety of advanced malignancies [1,2,3,4]. Some studies point to the idea that the expression of inhibitory ligands, such as CTLA-4 or PD-L1, by the tumor represents an adaptive response to tumor-specific T cells in the microenvironment [5, 6]. Treatment with a second driver of anti-tumor immune responses was shown to enhance the adaptive induction of the checkpoint molecule PD-L1 on tumor cells [7]. Contradictory at first sight, this upregulation of checkpoint molecules was critical for the efficacy of the subsequent treatment with checkpoint inhibitors and resulted in www.impactjournals.com/oncotarget regression of established tumors. Possible other secondary inducers of anti-tumor immunity might include cellular vaccines or chimeric antigen receptor T cells
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