New Nanoinducer of Interferons Found for Cancer Immunotherapy
Cancer immunotherapy such as immune checkpoint blockade (ICB) is a revolutionary treatment against tumors by re-enforcing immune surveillance and even inducing long-term disease control. Type I interferons (IFNs) are key coordinators of tumor-immune system interaction. Impaired IFN signaling is associated with poor prognosis in patients with colon cancer, melanoma, triple-negative breast cancer, etc. Current IFN supplementary therapy sometimes brings severe side effects and IFN-induced multigenic resistance program to ICB.
In a study published in Nature Nanotechnology on September 27, 2021, a research team led by LI Yaping and ZHANG Pengcheng from Shanghai Institute of Materia Medica of the Chinese Academy of Sciences (CAS) demonstrated that the paradoxical effects of IFN supplementary therapy could be addressed using a T lymphocyte membrane-decorated epigenetic nanoinducer of IFNs (OPEN)1.
The researchers first genetically engineered a programmed death receptor 1 (PD1)-overexpressing cytotoxic T cell line. The membrane of these cells was then used to envelope protein nanoparticle loaded with ORY-1001, an inhibitor of lysine-specific histone demethylase 1 (LSD1), to create OPEN. The team revealed that the OPEN improved the intratumoral accumulation of ORY-1001 and local production of IFNs after intravenous administration. They demonstrated that the IFNs increased tumor infiltration, proliferation and activity of tumor-specific cytotoxic T cells and antigen display of tumor cells. They proved that the IFN-induced programmed death ligand 1 (PDL1) and other immune checkpoint molecules were readily neutralized by subsequent OPEN. This sequential process specifically replenished intratumoral IFNs and alleviated IFN-induced immune evasion, and thus retarding tumor growth in multiple tumor models.
“The study demonstrates an elegant strategy to solve the paradoxical effects of IFN supplementary therapy using epigenetic nanoinducer of IFNs2. It is a milestone in the field of nanomedicine for safer andmore effective cancer immunotherapy”, said Prof. ZHAO Yuliang, an academician of CAS.
“This is the first research that elaborates the great potential of epigenetic nanomedicine in cancer immunotherapy3. The nanomedicine has significant clinical translation valuedue to its advantages in tumor targeted delivery and immune checkpoint blockade”, said Prof. HAO Xishan, an academician of Chinese Academy of Engineering (CAE).
Figure 1：(A)The preparation procedure of OPEN. (B) OPEN enters cancer cells after ligation with PDL1 and upregulates IFNs. The induced IFNs improves infiltration and activation of CTLs and PDL1, but the latter is blocked by subsequent OPEN. (C) OPEN improves tumor accumulation of the epigenetic drug, amounts of intratumoral IFNs and active CTLs, and blocks immune evasion. (D) OPEN suppresses the tumor growth of murine triple-negative breast cancer and melanoma. (Image by the team of LI Yaping and ZHANG Pengcheng)
1.Nat Nanotechnol 2021, DOI: 10.1038/s41565-021-00972-7
2.Sci China Chem, 2021, DOI: 10.1007/s11426-021-1108-0
3.Cancer Biol Med, 2021, DOI: 10.20892/j
Shanghai Institute of Materia Medica, Chinese Academy of Sciences