Harnessing type I interferon-mediated immunity to target malignant brain tumors

Abstract

Type I interferons have long been appreciated as a cytokine family that regulates antiviral immunity. Recently, their role in eliciting antitumor immune responses has gained increasing attention. Within the immunosuppressive tumor microenvironment (TME), interferons stimulate tumor-infiltrating lymphocytes to promote immune clearance and essentially reshape a "cold" TME into an immune-activating "hot" TME. In this review, we focus on gliomas, with an emphasis on malignant glioblastoma, as these brain tumors possess a highly invasive and heterogenous brain TME. We address how type I interferons regulate antitumor immune responses against malignant gliomas and reshape the overall immune landscape of the brain TME. Furthermore, we discuss how these findings can translate into future immunotherapies targeting brain tumors in general.

Keywords: brain tumors; glioblastoma; immunotherapy; tumor microenvironment; type I interferons.

Figure 1

Type I IFN signaling pathway. Secretion of type I interferons starts with stimulation of TLR4 expressed on the cell surface or TLR3, TLR7, and TLR9 that is expressed within endosomes. Stimulation of TLR3, TLR4, TLR7, and TLR9 leads to induction of type I IFN signaling. Upon ligand recognition, triggering of these TLRs activates a downstream pathway that results in the production of type I interferons. Type I interferons, in turn, signal through IFNAR to activate JAK-STAT pathway, leading to dimerization of STAT. Binding with IRF9 results in ISGF3 complex that translocates to the nucleus to bind to interferon-stimulated response elements (ISRE), leading to the induction of interferon-stimulated genes (ISGs).

Figure 2

Protumoral and antitumoral roles of type I IFNs in the glioma tumor microenvironment. Tumor promoting roles of IFNs. (A) Chronic intrinsic tumor cell IFN signaling leads to dysfunction of T cells, promoting increased expression of exhaustion markers such as TIM-3, LAG-3, CTLA-4, and TIGIT. This ultimately leads to immune checkpoint blockade resistance. (B) All cell types within the TME express IFNAR and have type I IFN signaling. The glioma tumor microenvironment promotes the release of protumoral factors. Reactive astrocytes release TGFβ, STAT3, and osteopontin (SPP1) are known to contribute to tumor progression. In addition, release of IL-10 by tumor-infiltrating DCs promote tumor growth along with enhanced TGFβ expression by protumoral M2 TAMs. Tumor-promoting M2 microglia are known to release proinflammatory IL-12, IL-10, and IL-23. (C) The nearby release of TGFβ promotes Treg proliferation contributing to a tumor promoting TME. Tumor restricting roles of IFNs. (A) Type I IFNs potentiate the cytotoxicity of innate cells, such as NK cells, CD8 T cells, CD4 T cells, and even innate-like pDCs. (B) Cross-presentation ability of tumor-infiltrating dendritic cells is enhanced through upregulation of maturation markers, that in turn, enhance CD8 T cell effector responses. (C) M1 TAMs and M1 microglia have been suggested to acquire an enhanced ISG signature in the presence of type I interferons in the brain TME. (D) The overall secretion of type I IFNs, whether they are tumor cell-derived or host-derived, can either directly or indirectly affect the functions of other nearby immune cells. Thus, these cytokines exhibit a paracrine effect. Secretion of IFNs can suppress Treg function and promote an antitumoral environment.

Figure 3

Glioma targeted therapy. (A) Apart from current standard of care, administration of recombinant IFNβ and IFNα2 has been approved by the FDA for glioma treatment. Usually used as adjuvants, antitumor activity of these recombinant proteins has been shown in several clinical studies and examined for overall systemic toxicity. (B) Engineering of myeloid cells to deliver interferons to the glioma tumor microenvironment has shown therapeutic potential. Recent techniques have leveraged the ability of tumor-associated macrophages and Tie2-expressing monocytes to reach the TME and release type I interferons, inducing glioma cell dysfunction. (C) Administration of anti-PD1 monoclonal antibodies to prevent T cell deactivation has shown little success in gliomas than expected. This could be due to the cell intrinsic type I IFN signaling within tumor cells that contribute to ICB resistance. (D) Dendritic cell-based vaccines alleviate the immunosuppression of the glioma TME by enhancing T cell responses. Exposure to tumor antigens and pulsing of interferons to ex vivo isolated immature DCs leads to their maturation and upregulation to potentiate effector T cell responses against malignant glioma tumor cells.