Approaches of the Innate Immune System to Ameliorate Adaptive Immunotherapy for B-Cell Non-Hodgkin Lymphoma in Their Microenvironment

SIMPLE SUMMARY: The innate immune checkpoint blockade anti-CD47 antibodies combined with the anti-CD20 antibody rituximab can invigorate macrophage phagocytosis. Generally applied as vaccine adjuvants, TLR9 agonist CpG-oligodeoxynucleotides (CpG-ODNs) stimulate antigen presenting cells (APCs) and plasmacytoid dendritic cells (pDCs) to secrete interferon (IFN)-α/β, which activates natural killer (NK) cells. This innate immune activation and pDC maturation leads to potentiation of the adaptive immune response. In fact, stimulator of interferon gene agonists also induce APCs to secrete IFN-α/β. CpG-ODNs, combined with rituximab or irradiation, demonstrated clinical efficacy in indolent B-cell non-Hodgkin lymphoma patients. Furthermore, patients with mantle cell lymphoma presenting Ig-derived neoantigens and vaccinated with CpG-ODN priming T cells maintained minimal residual disease. Additionally, IFN-α–conditioned DC vaccination as well as 4-1BB and OX40 agonist antibodies activate NK cells as well as T cells. Collectively, these innate activators are promising agents for enhancing anti-B-cell-lymphoma adaptive immunity, such as chimeric antigen receptor-T-cell therapy. ABSTRACT: A dominant paradigm being developed in immunotherapy for hematologic malignancies is of adaptive immunotherapy that involves chimeric antigen receptor (CAR) T cells and bispecific T-cell engagers. CAR T-cell therapy has yielded results that surpass those of the existing salvage immunochemotherapy for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after first-line immunochemotherapy, while offering a therapeutic option for patients with follicular lymphoma (FL) and mantle cell lymphoma (MCL). However, the role of the innate immune system has been shown to prolong CAR T-cell persistence. Cluster of differentiation (CD) 47-blocking antibodies, which are a promising therapeutic armamentarium for DLBCL, are novel innate immune checkpoint inhibitors that allow macrophages to phagocytose tumor cells. Intratumoral Toll-like receptor 9 agonist CpG oligodeoxynucleotide plays a pivotal role in FL, and vaccination may be required in MCL. Additionally, local stimulator of interferon gene agonists, which induce a systemic anti-lymphoma CD8(+) T-cell response, and the costimulatory molecule 4-1BB/CD137 or OX40/CD134 agonistic antibodies represent attractive agents for dendritic cell activations, which subsequently, facilitates initiation of productive T-cell priming and NK cells. This review describes the exploitation of approaches that trigger innate immune activation for adaptive immune cells to operate maximally in the tumor microenvironment of these lymphomas.