CRISPR/Cas9‐HPV‐liposome enhances antitumor immunity and treatment of HPV infection‐associated cervical cancer

Abstract

Increasing evidence shows that human papillomavirus (HPV) E6/E7 deletion in cervical cancer cells may be related to the immunosuppressive tumor microenvironment and adverse reactions or resistance to immune checkpoint blockade. Here, we demonstrate that liposome delivery of CRISPR/cas9 can effectively knock out HPV, which, in turn, induces autophagy and triggers cell death‐related immune activation by releasing damage‐related molecular patterns. The results of in vivo experiments showed that HPV‐targeting guide RNA–liposomes could promote CD8+ T cell infiltration in tumor tissues; enhance the expression of proinflammatory cytokines, such as interleukin‐12, tumor necrosis factor‐α, and interferon‐γ, and reduce regulatory T cells and myeloid suppressor cells. The combination of HPV‐targeting guide RNA–liposomes with immune checkpoint inhibitors and antiprogrammed death‐1 antibodies produced highly effective antitumor effects. In addition, combination therapy induced immune memory in the cervical cancer model.

Advanced technologies towards improved HPV diagnostics

“…By using liposome delivery of CRISPR-Cas9, authors effectively knocked out HPV, which, in turn, induced autophagy and triggered cell death-related immune activation by releasing damagerelated molecular patterns. 143 The CRISPR smear samples with 97.8% sensitivity and 98.1% specificity. 133 A similar approach was introduced by Zhao et al 141 by combining RPA and fluorescence readout into a microfluidic dual-droplet device.…”

“…Interestingly, CRISPR‐Cas technology was recently used also in a treatment of HPV infection‐associated cervical cancer. By using liposome delivery of CRISPR‐Cas9, authors effectively knocked out HPV, which, in turn, induced autophagy and triggered cell death‐related immune activation by releasing damage‐related molecular patterns 143 …”

Biogenic materials for CRISPR delivery and therapeutics

“…115 Moreover, liposome-based delivery of CRISPR/Cas9 can effectively knock out HPV, and then HPV in turn induces autophagy and triggers cell death-related immune activation by releasing damage-related molecular patterns, which ultimately has a good effect on the treatment of cervical cancer. 116 Lipid nanoparticles (LNPs) are clinically approved non-viral nucleic acid delivery systems that can deliver large payloads. In order to enhance the specific targeting of liver disease tissues, an effective cLNP system was developed, which can inhibit tumor growth by delivering Cas9 mRNA and sgRNAs targeting Plk1, and can overcome the limitations of current treatment methods in clinic-related tumor models.…”

“…115 Moreover, liposome-based delivery of CRISPR/Cas9 can effectively knock out HPV, and then HPV in turn induces autophagy and triggers cell death-related immune activation by releasing damage-related molecular patterns, which ultimately has a good effect on the treatment of cervical cancer. 116…”

Human Papillomavirus Infection: Epidemiology, Biology, Host Interactions, Cancer Development, Prevention, and Therapeutics

“…10,32,[55][56][57][58] Targeted therapies, such as immune checkpoint inhibitors or specific molecular targeted drugs, may be used in certain cases to block the growth signals of cancer cells or enhance the immune response against the tumor. [59][60][61][62] HPV-related cancers can be responsive to immunotherapy approaches. Therapies such as immune checkpoint inhibitors, which block proteins that inhibit the immune response, can help unleash the immune system's ability to recognize and attack cancer cells.…”