Next-generation antigen-presenting cell immune therapeutics for gliomas

Abstract

Antigen presentation machinery and professional antigen-presenting cells (APCs) are fundamental for an efficacious immune response against cancers, especially in the context of T cell-centric immunotherapy. Dendritic cells (DCs), the gold standard APCs, play a crucial role in initiating and maintaining a productive antigen-specific adaptive immunity. In recent decades, ex vivo-differentiated DCs from circulating CD14+ monocytes have become the reference for APC-based immunotherapy. DCs loaded with tumor-associated antigens, synthetic peptides, or RNA activate T cells with antitumor properties. This strategy has paved the way for the development of alternative antigen-presenting vaccination strategies, such as monocytes, B cells, and artificial APCs, that have shown effective therapeutic outcomes in preclinical cancer models. The search for alternative APC platforms was initiated by the overall limited clinical impact of DC vaccines, especially in indications such as gliomas, a primary brain tumor known for resistance to any immune intervention. In this Review, we navigate the APC immune therapeutics' past, present, and future in the context of primary brain tumors.

Figure 1. MHC-dependent antigen presentation.

CD8⁺ (left) and CD4⁺ (right) T cell receptors are activated via antigens presented by MHC I and MHC II, respectively (first signal). Together with the costimulatory signal through CD28 engagement (second signal) and cytokines (third signal), this machinery can activate different T cells into different functional subsets (bottom rows of figure). For more details on naive CD4⁺ and CD8⁺ T cell differentiation and effector functions, see reviews (6, 141). AhR, aryl hydrocarbon receptor; BCL-6, B cell lymphoma 6; Eomes, eomesodermin; Foxp3, forkhead box P3; GATA3, GATA-binding protein 3; IRF4, interferon-regulatory factor 4; ROR, retinoic acid receptor–related orphan receptor; Tc, cytotoxic T cells; TCR, T cell receptor; Tfh, T follicular helper.

Figure 2. B cell vaccine generation.

B cell–based vaccines (B_Vax) are produced from 4-1BBL⁺ B cells isolated from secondary lymphoid organs of tumor-bearing mice or GBM patients’ blood. B cells are activated ex vivo using CD40 agonism, the B cell survival factor BAFF (yellow), and IFN-γ (blue). After activation, B cells are pulsed with tumor lysates.

Figure 3. B cell vaccine immune effector functions.

B_Vax can exert an antitumor immune response via cellular immunity (activation of CD8⁺ T cells) and humoral immunity (production of tumor-reactive antibodies). PFN, perforin.