Mitigating SOX2-potentiated Immune Escape of Head and Neck Squamous Cell Carcinoma with a STING-inducing Nanosatellite Vaccine

Abstract

The response rates of Head and Neck Squamous Cell Carcinoma (HNSCC) to checkpoint blockade are below 20%. We aim to develop a mechanism-based vaccine to prevent HNSCC immune escape. We performed RNA-Seq of sensitive and resistant HNSCC cells to discover central pathways promoting resistance to immune killing. Using biochemistry, animal models, HNSCC microarray, and immune cell deconvolution, we assessed the role of SOX2 in inhibiting STING-type I interferon (IFN-I) signaling-mediated antitumor immunity. To bypass SOX2-potentiated STING suppression, we engineered a novel tumor antigen-targeted nanosatellite vehicle to enhance the efficacy of STING agonist and sensitize SOX2-expressing HNSCC to checkpoint blockade. The DNA-sensing defense response is the most suppressed pathway in immune-resistant HNSCC cells. We identified SOX2 as a novel inhibitor of STING. SOX2 facilitates autophagy-dependent degradation of STING and inhibits IFN-I signaling. SOX2 potentiates an immunosuppressive microenvironment and promotes HNSCC growth in an IFN-I-dependent fashion. Our unique nanosatellite vehicle significantly enhances the efficacy of STING agonist. We show that the E6/E7-targeted nanosatellite vaccine expands the tumor-specific CD8 T cells by over 12-fold in the tumor microenvironment and reduces tumor burden. A combination of nanosatellite vaccine with anti-PD-L1 significantly expands tumor-specific CTLs and limits the populations expressing markers for exhaustion, resulting in more effective tumor control and improved survival. SOX2 dampens the immunogenicity of HNSCC by targeting the STING pathway for degradation. The nanosatellite vaccine offers a novel and effective approach to enhance the adjuvant potential of STING agonist and break cancer tolerance to immunotherapy. .

CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review

“…The M2 cells repress the immune system (Genard et al, ), and their high existence within the tumor is associated with poor prognosis (B. Tan, Shi, et al, ). M1 cell recruitment and CTL production are the two simultaneous processes occurring in the tumor stroma, and the two phenomena are under the influence of IFN release to the TME (Y. S. Tan, Sansanaphongpricha, et al, ). CTLs within the tumor stroma send paracrine signals for changing macrophage polarity toward the antitumor M1 cells, and that the cells have negative cross‐talking with M2 cells in which a reduction in the number of M2 cells in the TME would cause a rise in the recruitment of CTLs to this milieu to exert antitumor immunity for regression of tumor.…”

HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING

“…The median follow-up at the time of analysis was 60.1 months. STING staining in HNSCC parenchyma and TME was independently defined and quantitated using Aperio ImageScope as we described previously (14,27). Upon removal of cores with insufficient tumor tissue, STING staining scores were available from 264 HNSCC specimens.…”

“…We found that STING expression in the tumor parenchyma remained a favorable prognosticator (P = 0.049), while the STING staining scores of the antigen-targeted cytotoxic T lymphocytes (CTLs); it remains unexplained why most HNSCCs are hypoimmunogenic despite the presence of high mutation burdens and the presentation of HPV-associated neoantigens (13). To explain this dichotomy, we recently demonstrated that HNSCC cells evade immune surveillance through suppression of the STING/IFN-I pathway, a key adaptive resistance mechanism that limits effector T cell expansion (14). IFN-I is produced by both cancer cells and antigen-presenting cells (APCs).…”

“…Because of the highly polar molecular properties of cGAMP, which may prevent it from entering the cytoplasm effectively to maximally activate STING, we engineered unique nanoparticles and slow-release delivery systems to improve the pharmacodynamics of STING agonists. These efforts improved the delivery of cGAMP in vivo and sensitized hypoimmunogenic HNSCCs to immune checkpoint blockade (14,24).…”

RACK1 promotes cancer progression by increasing the M2/M1 macrophage ratio via the NF‐κB pathway in oral squamous cell carcinoma

“…It is well acknowledged that TAM mainly have an M2‐like phenotype. Clinical and experimental evidence has shown that TAM promote the development and progression of most tumor types (Ruffell and Coussens, ; Tan et al , ). There are many macrophages in OSCC tissues, and TAM are also believed to participate in OSCC progression (Kubota and Moriyama, ; Petruzzi et al , ; Sun et al , ).…”