A Physiologically Responsive Nanocomposite Hydrogel for Treatment of Head and Neck Squamous Cell Carcinoma via Proteolysis‐Targeting Chimeras Enhanced Immunotherapy
Yaping WuXiaowei ChangGuizhu YangLi ChenQi WuJiamin GaoRan TianWenyun MuJ. Justin GoodingXin ChenShuyang Sun
47
Citation
56
Reference
10
Related Paper
Citation Trend
Abstract:
Although immunotherapy has revolutionized oncotherapy, only ≈15% of head and neck squamous cell carcinoma (HNSCC) patients benefit from the current therapies. An immunosuppressive tumor microenvironment (TME) and dysregulation of the polycomb ring finger oncogene BMI1 are potential reasons for the failure. Herein, to promote immunotherapeutic efficacy against HNSCC, an injectable nanocomposite hydrogel is developed with a polymer framework (PLGA-PEG-PLGA) that is loaded with both imiquimod encapsulated CaCO3 nanoparticles (RC) and cancer cell membrane (CCM)-coated mesoporous silica nanoparticles containing a peptide-based proteolysis-targeting chimeras (PROTAC) for BMI1 and paclitaxel (PepM@PacC). Upon injection, this nanocomposite hydrogel undergoes in situ gelation, after which it degrades in the TME over time, releasing RC and PepM@PacC nanoparticles to respectively perform immunotherapy and chemotherapy. Specifically, the RC particles selectively manipulate tumor-associated macrophages and dendritic cells to activate a T-cell immune response, while CCM-mediated homologous targeting and endocytosis delivers the PepM@PacC particles into cancer cells, where endogenous glutathione promotes disulfide bond cleavage to release the PROTAC peptide for BMI1 degradation and frees the paclitaxel from the particle pores to elicit apoptosis meanwhile enhance immunotherapy. Thus, the nanocomposite hydrogel, which is designed to exploit multiple known vulnerabilities of HNSCC, succeeds in suppressing both growth and metastasis of HNSCC.The tumor microenvironment (TME) chiefly consists of tumor cells and tumor-infiltrating immune cells admixed with the stromal component. A recent clinical trial has shown that the tumor immune cell infiltration (ICI) is correlated with the sensitivity to immunotherapy and the head and neck squamous cell carcinoma (HNSC) prognosis. However, to date, the immune infiltrative landscape of HNSC has not yet been elucidated. Herein, we proposed two computational algorithms to unravel the ICI landscape of 1,029 HNSC patients. Three ICI patterns were defined, and the ICI scores were determined by using principal-component analysis. A high ICI score was characterized by an increased tumor mutation burden (TMB) and the immune-activating signaling pathways. Activation of transforming growth factor-β (TGF-β) and WNT signaling pathways were observed in low ICI score subtypes, indicating T cell suppression, and may be responsible for poor prognosis. Two immunotherapy cohorts confirmed patients with higher ICI scores demonstrated significant therapeutic advantages and clinical benefits. This study demonstrated that the ICI scores serve as an effective prognostic biomarker and predictive indicator for immunotherapy. Evaluating the ICI patterns of a larger cohort of samples will extend our understanding of TME, and it may provide directions to the current research investigations on immunotherapeutic strategies for HNSC.
Cite
Citations (202)
In the past decades, prognosis of head and neck squamous cell carcinoma (HNSCC) has not improved despite substantial progress in treatment options. Since antitumoral immunity was described, immunotherapy has shown promising results as an adjunctive treatment in various cancer types. Tumor-associated antigens (TAAs) have been identified and shown to stimulate selective T-cell-mediated antitumoral immune response. This article briefly reviews the work done in the field of immunotherapy of HNSCC in the past few years. It gives confidence that immunotherapy may play an important role in the treatment of head and neck squamous cell carcinoma. Among various TAAs, the family of cancer testis antigens (CTAs) may be promising candidates for specific immune therapy in HNSCC. Ongoing studies will confirm whether CTAs may generate an immune response in clinical vaccine trials.
Cancer Immunotherapy
Cite
Citations (1)
Modulation of the tumor microenvironment is becoming an increasingly popular research topic in the field of immunotherapy, and studies regarding immune checkpoint blockades and cancer immunotherapy have pushed cancer immunotherapy to a climax. Simultaneously, the manipulation of the immune regulatory pathway can create an effective immunotherapy strategy; however, the tumor microenvironment serves an important role in suppressing the antitumor immunity by its significant heterogeneity. A number of patients with cancer do not have a good response to monotherapy approaches; therefore, combination strategies are required to achieve optimal therapeutic benefits. Targeting the tumor microenvironment may provide a novel strategy for immunotherapy, break down the resistance of conventional cancer therapy and produce the foundation for personalized precision medicine. The present review summarized the research regarding cancer immunotherapy from the perspective of how the tumor microenvironment affects the immune response, with the aim of proposing a novel strategy for cancer immunotherapy and combination therapy.
Cancer Immunotherapy
Immune checkpoint
Cite
Citations (71)
Cancer immunotherapy has shown impressive anti-tumor activity in patients with advanced and early-stage malignant tumors, thus improving long-term survival. However, current cancer immunotherapy is limited by barriers such as low tumor specificity, poor response rate, and systemic toxicities, which result in the development of primary, adaptive, or acquired resistance. Immunotherapy resistance has complex mechanisms that depend on the interaction between tumor cells and the tumor microenvironment (TME). Therefore, targeting TME has recently received attention as a feasibility strategy for re-sensitizing resistant neoplastic niches to existing cancer immunotherapy. With the development of nanotechnology, nanoplatforms possess outstanding features, including high loading capacity, tunable porosity, and specific targeting to the desired locus. Therefore, nanoplatforms can significantly improve the effectiveness of immunotherapy while reducing its toxic and side effects on non-target cells that receive intense attention in cancer immunotherapy. This review explores the mechanisms of tumor microenvironment reprogramming in immunotherapy resistance, including TAMs, CAFs, vasculature, and hypoxia. We also examined whether the application of nano-drugs combined with current regimens is improving immunotherapy clinical outcomes in solid tumors.
Cancer Immunotherapy
Reprogramming
Cite
Citations (40)
Cite
Citations (20)
Immunotherapy approaches for head and neck squamous cell carcinoma (HNSCC) are rapidly advancing. Human papillomavirus (HPV) has been identified as a causative agent in a subset of oropharyngeal cancers (OPC). HPV-positive OPC comprises a distinct clinical and pathologic disease entity and has a unique immunophenotype. Immunotherapy with anti-PD1 checkpoint inhibitors has exhibited improved outcomes for patients with advanced HNSCC, irrespective of HPV status. To date, the clinical management of HPV-positive HNSCC and HPV-negative HNSCC has been identical, despite differences in the tumor antigens, immune microenvironment, and immune signatures of these two biologically distinct tumor types. Numerous clinical trials are underway to further refine the application of immunotherapy and develop new immunotherapy approaches. The aim of this review is to highlight the developing role of immunotherapy in HPV-positive HNSCC along with the clinical evidence and preclinical scientific rationale behind emerging therapeutic approaches, with emphasis on promising HPV-specific immune activators that exploit the universal presence of foreign, non-self tumor antigens.
Cancer Immunotherapy
Cite
Citations (31)
Cancer Immunotherapy
Cite
Citations (266)
Abstract Background: The tumor microenvironment (TME) has achieved remarkable results in the research of cancer progression in the past few years. it is crucial to understand the nature and function of TME in tumors because of precise treatment strategies for individual cancers having received widespread attention, including immunotherapy. The immune infiltrative profiles of neuroblastoma (NB) have not yet been completely illustrated. The purpose of this research is to analyses tumor immune cell infiltration (ICI) in the microenvironment of NB. Methods: We applied CIBERSORT and ESTIMATE algorithms to evaluate the ICI status of 438 NB samples. Three ICI models were selected and ICI scores were acquired. Subgroups with high ICI scores based on immune activation signaling pathways have better overall survival. Results: The genes of immunosuppressive glycosaminoglycan biosynthesis heparan sulfate signaling pathway were markedly enriched in the low ICI score subgroup. It was inferred that compared with low ICI NB subtypes, patients with high ICI NB subtypes were more likely to respond to immunotherapy and a better prognosis. Conclusion: Notably, our ICI scores not only provided new clinical and theoretical basis for mining NB prognostic markers related to the microenvironment, but also aided new ideas for the development of new NB precision immunotherapy methods.
Cancer Immunotherapy
Cite
Citations (0)
Tumor immunotherapy is considered to be a novel and promising therapy for tumors and it has recently become a hot research topic. The clinical success of tumor immunotherapy has been notable, but it has been less than totally satisfactory because tumor immunotherapy has performed poorly in numerous patients although it has shown appreciable efficacy in some patients. A minority of patients demonstrate durable responses but the majority of patients do not respond to tumor immunotherapy as the tumor immune microenvironment is different in different patients for different tumor types. The success of tumor immunotherapy may be affected by the heterogeneity of the tumor immune microenvironment and its components, as these vary widely during neoplastic progression. The deepening of research and the development of technology have improved our understanding of the complexity and heterogeneity of the tumor immune microenvironment and its components, and their effects on response to tumor immunotherapy. Therefore, investigating the tumor immune microenvironment and its components and elucidating their association with tumor immunotherapy should improve the ability to study, predict and guide immunotherapeutic responsiveness, and uncover new therapeutic targets.
Cancer Immunotherapy
Tumor progression
Cite
Citations (24)