Empowering therapeutic antibodies with IFN-α for cancer immunotherapy

Abstract

Type 1 IFNs stimulate secretion of IP-10 (CXCL10) which is a critical chemokine to recruit effector T cells to the tumor microenvironment and IP-10 knockout mice exhibit a phenotype with compromised effector T cell generation and trafficking. Type 1 IFNs also induce MHC class 1 upregulation on tumor cells which can enhance anti-tumor CD8 T cell effector response in the tumor microenvironment. Although type 1 IFNs show great promise in potentiating anti-tumor immune response, systemic delivery of type 1 IFNs is associated with toxicity thereby limiting clinical application. In this study, we fused tumor targeting antibodies with IFN-α and showed that the fusion proteins can be produced with high yields and purity. IFN fusions selectively induced IP-10 secretion from antigen positive tumor cells, which was critical in recruiting the effector T cells to the tumor microenvironment. Further, we found that treatment with the anti-PDL1-IFN- α fusion at concentrations as low as 1 pM exhibited potent activity in mediating OT1 CD8 + T cell killing against OVA expressing tumor cells, while control IFN fusion did not exhibit any activity at the same concentration. Furthermore, the IFN-α fusion antibody was well tolerated in vivo and demonstrated anti-tumor efficacy in an anti-PD-L1 resistant syngeneic mouse tumor model. One of the potential mechanisms for the enhanced CD8 T cell killing by anti-PD-L1 IFN fusion was up-regulation of MHC class I/tumor antigen complex. Our data supports the hypothesis of targeting type 1 IFN to the tumor microenvironment may enhance effector T cell functions for anti-tumor immune response.

Polysaccharide Isolated From Tetrastigma hemsleyanum Activates TLR4 in Macrophage Cell Lines and Enhances Immune Responses in OVA-Immunized and LLC-Bearing Mouse Models

“…IP-10 is a key chemokine recruiting effector T cells to the tumor microenvironment. Type I IFNs can not only further promote the secretion of IP-10 but also upregulate the expression of MHCⅠ on tumor cells, thus enhancing the antitumor CD8 + T cell effector response ( Najbauer et al, 2019 ). Therefore, TLR4 receptor agonists with the ability to activate both MyD88-dependent and -independent pathways are also promising drugs for cancer immunotherapy.…”

Effect of apigenin on whole transcriptome profile of TNFα‑activated MDA‑MB‑468 triple negative breast cancer cells

“…In this work, for example, we show that apigenin suppressed the TNFα mediated rise in a potent tumor suppressor: CXCL10. While previous studies consistently that CXCL10 is up-regulated in normal vs. tumor tissue (76,77) this particular protein acts as the major tumor suppressor, evoked by IFN-γ treatment and somehow plays a role in the re-expression of MHC-1, PD-L1, the infiltration of anti-tumoral CD4(+) and CD8(+) T cells (78,79), NK cells, cytotoxic lymphocytes (CTLs) to the tumor to turn on immune surveillance and heighted survival odds in diverse human cancers (80)(81)(82). While the beneficial effects of apigenin in cancer are consistently reported, any compound that would turn off the CXCL9, -10, -11/CXCR3 axis could harm the host immunes system to destroy self-malignant tumor tissue (83).…”

Double-edged effects of interferons on the regulation of cancer-immunity cycle

“…47,48 Additionally, both type I IFN (IFN-α and IFN-β) and type II IFN have been reported to enhance the efficacy of anti-PD1 or anti-PD-L1 in various cancer types, such as melanoma and pancreatic cancer. [13][14][15][16][17] Secondly, various IFN stimulating strategies based on targeting PRRs have been developed to treat cancer, and accumulating evidence indicate that PRR agonists synergize with other therapy approaches and attribute to a better therapeutic efficacy. Deng et al found that the administration of STING agonist (2ʹ3' cGAMP, 10μg) synergized with radiation (20 Gy) and significantly boost anti-cancer immune response in murine colon cancer bearing mouse models.…”

“…[10][11][12] Moreover, IFNs enhance the therapeutic sensitivity of ICBs in various cancer types. [13][14][15][16][17] These studies suggest that IFN signaling plays an important role in cancer immunotherapy. In this review, we focus on IFNs and cancer immunity, and elaborate on the roles of IFNs in regulating the cancer-immunity cycle.…”