CpG-based immunotherapy impairs antitumor activity of BRAF inhibitors in a B-cell-dependent manner

Abstract

Combining immunotherapy with targeted therapy has increasingly become an appealing therapeutic paradigm for cancer treatment due to its great potential for generating durable and synergistic antitumor response. In this study, however, we unexpectedly found that two types of CpG-based tumor peptide vaccine treatments consistently negated the antitumor activity of a selective BRAF inhibitor in tumors with BRAF mutation rather than showing a synergistic antitumor effect. Our further studies demonstrated that CpG alone was sufficient to dampen BRAF inhibitor-induced antitumor responses, suggesting that the impaired antitumor activity of the BRAF inhibitor observed in mice receiving CpG-based peptide vaccine is mainly dependent upon the use of CpG. Mechanistically, CpG increased the number of circulating B cells, which produced elevated amounts of TNFα that contributed to the increased tumor resistance to BRAF inhibitors. More importantly, B cell depletion or TNFα neutralization can restore the antitumor effect of BRAF inhibition in mice receiving CpG treatment, indicating that TNFα-secreting B cells play an indispensable role in BRAF inhibitor resistance induced by CpG. Taken together, our results strongly suggest that precautions must be implemented when designing combinatorial approaches for cancer treatment, because distinct regimens, despite their respective therapeutic benefit as monotherapy, may together provide antagonistic clinical outcomes.

Anti-OX40 Antibody Directly Enhances The Function of Tumor-Reactive CD8+ T Cells and Synergizes with PI3Kβ Inhibition in PTEN Loss Melanoma

“…A similar potentially antagonistic antitumor effect has been observed with the combination of immunotherapy and targeted therapy. In that, although both CpG-based tumor vaccine and BRAF inhibitor have therapeutic benefit as monotherapies in patients with cancer, combining CpG with BRAF inhibitor negates the antitumor effect of BRAF inhibitor in Braf-mutant tumors in a B-cell-dependent manner (38). Therefore, to develop potent therapeutic strategies for OX40-based cancer treatment, we need to not only rationally choose combination partners with complementing effects, but also optimize treatment schedules to maximize the antitumor effect of anti-OX40.…”

Anti-Cancer Auto-Antibodies: Roles, Applications and Open Issues

“…The concept of the host immune system generating anti-cancer immune cells and antibodies [ 12 ] is one of the pillars of immune-based targeted therapies [ 13 , 14 ], as cell- and antibody-based drugs have been shown to inhibit cancer growth through different complementary mechanisms. However, there is growing evidence suggesting that B cells and antibodies can also be involved in tumor promotion and resistance to cancer therapy [ 15 , 16 , 17 ], with the observation that B cell depletion can suppress tumor growth in mice [ 18 ]. In ovarian cancer, the presence of CD20 + B cells has been associated with an increased survival, while in contrast, the presence of regulatory B cells (B regs ) induces immunosuppressive effects, supporting tumor growth [ 19 ].…”

CpG Oligodeoxynucleotides for Anticancer Monotherapy from Preclinical Stages to Clinical Trials

“…Another study verified that class A CpG ODNs enhanced NK cell cytotoxicity against Tu167 and K562 cell lines in vitro [45]. However, a few reports have indicated that CpG ODN treatments may not result in B cell-based antitumor activities [46,47]. Contrarily, TNFαsecreting B cells induced by ODN 2216 may show resistance to certain chemotherapies in mice models [46].…”

“…However, a few reports have indicated that CpG ODN treatments may not result in B cell-based antitumor activities [46,47]. Contrarily, TNFαsecreting B cells induced by ODN 2216 may show resistance to certain chemotherapies in mice models [46].…”