CD40-activated B cells induce anti-tumor immunityin vivo

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.

B Cell-Based Cancer Immunotherapy

“…Body weight and survival remained unchained under all tested conditions. No abnormal lymphocytic infiltration, structural tissue injury, or indications of inflammation could be detected in histological analyses of heart, lung, liver, spleen, and kidney [68]. These results are in line with a study where administration of RNA-loaded CD40B cells was well tolerated by dogs with non-Hodgkin’s lymphoma and no long-term complications were observed in the follow-up [69].…”

“…However, these studies used soluble anti-CD40 antibodies for the activation of B cells, which was demonstrated to result in weaker CD40 stimulation than activation by CD40L-expressing feeder cells [21, 31]. When using CD40L-expressing feeder cells for activation, vaccination with tumor antigen-pulsed CD40B cells before B16 melanomas or E.G7 lymphomas were injected [68] resulted in significantly delayed growth in both tumor models. The rate of tumor control by CD40B cell vaccination was comparable to that induced by DCs.…”

A new perspective: Exploring future therapeutic strategies for cancer by understanding the dual role of B lymphocytes in tumor immunity

“…At the same time, the antigen‐specific B cells can also differentiate into plasma cells to reinforce antitumor effects and to diminish established tumors. Indeed, CD40‐activated B cells have been widely studied, which activating and promoting the proliferation of T cell to induce antitumor immunity by acting as APCs …”

Inflammation enhances the vaccination potential of CD40‐activated B cells in mice

“…Such activated B cells increased expression of costimulatory and MHC molecules [16,[18][19][20] rendering them attractive for vaccination. It was shown by several groups that mouse and human CD40 activated B (CD40-B) cells could present a variety of MHC class I and II epitopes to T cells [16][17][18][19][20][21][22][23][24]. Furthermore, we, and others, have shown that CD40-B cells can prime naive CD8 + T-cell response in vivo [16][17][18][19]22].…”

“…It was shown by several groups that mouse and human CD40 activated B (CD40-B) cells could present a variety of MHC class I and II epitopes to T cells [16][17][18][19][20][21][22][23][24]. Furthermore, we, and others, have shown that CD40-B cells can prime naive CD8 + T-cell response in vivo [16][17][18][19]22]. Preclinical vaccination studies in mice and dogs have shown their potential for cancer immunotherapy [16,18,22,25].…”