Abstract
The unsatisfactory response rate of immune checkpoint blockade (ICB) immunotherapy severely limits its clinical application as a tumor therapy. Here, we generate a vaccine-based nanosystem by integrating siRNA for Cd274 into the commercial human papillomavirus (HPV) L1 (HPV16 L1) protein. This nanosystem has good biosafety and enhances the therapeutic response rate of anti-tumor immunotherapy. The HPV16 L1 protein activates innate immunity through the type I interferon pathway and exhibits an efficient anti-cancer effect when cooperating with ICB therapy. For both resectable and unresectable breast tumors, the nanosystem decreases 71% tumor recurrence and extends progression-free survival by 67%. Most importantly, the nanosystem successfully induces high response rates in various genetically modified breast cancer models with different antigen loads. The strong immune stimulation elicited by this vaccine-based nanosystem might constitute an approach to significantly improve current ICB immunotherapy.
Highlights
The unsatisfactory response rate of immune checkpoint blockade (ICB) immunotherapy severely limits its clinical application as a tumor therapy
Utilizing the specific binding between human papillomavirus (HPV) capsid and α6 integrin over-expressed in TNBC17, PEGylated HPV16 L1 protein is assembled with siRNA oligonucleotides for inhibiting the expression of tumorspecific PDL118,19
IRF7 is a well-known transcription factor that regulates the secretion of interferon (IFN) in response to viruses[20], which implies that the activation of innate immunity by viruses may further amplify the anticancer immunity (Supplementary Fig. 1)
Summary
The unsatisfactory response rate of immune checkpoint blockade (ICB) immunotherapy severely limits its clinical application as a tumor therapy. We generate a vaccine-based nanosystem by integrating siRNA for Cd274 into the commercial human papillomavirus (HPV) L1 (HPV16 L1) protein This nanosystem has good biosafety and enhances the therapeutic response rate of anti-tumor immunotherapy. Immune checkpoint blockade (ICB), especially the pharmaceutical targeting of programmed cell death protein 1 or programmed cell death protein 1(PD1/PDL1) has displayed satisfactory effects in treating patients with melanoma, non-small cell lung cancer and triple-negative breast cancer (TNBC)[7]. Despite these achievements, a primary problem facing ICB therapy in clinical trials is the extremely low response rate. The design of siRNA@HPVP establishes a convenient method for increasing the response rate of ICB therapy through the combination of the microbial-based vaccines in use
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