Open AccessEmpowering therapeutic antibodies with IFN-α for cancer immunotherapy
Author(s) -
Jun Guo,
Xiao Yu,
Ramesh Iyer,
Xin Lü,
Marc Lake,
Uri S. Ladror,
John E. Harlan,
Tanushree Samanta,
Medha J. Tomlinson,
Gail Bukofzer,
Cherrie K. Donawho,
Alexander R. Shoemaker,
Tzu-Hsuan Huang
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0219829
Subject(s) - tumor microenvironment , cd8 , cancer immunotherapy , cancer research , biology , immunotherapy , cytotoxic t cell , mhc class i , t cell , cxcl10 , chemokine , immune system , antigen , immunology , in vitro , biochemistry
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.