Induction of therapeutic immunity and cancer eradication through biofunctionalized liposome-like nanovesicles derived from irradiated-cancer cells.

Immunotherapy has revolutionized the treatment of cancer. However, its efficacy remains to be optimized. There are at least two major challenges in effectively eradicating cancer cells by immunotherapy. Firstly, cancer cells evade immune cell killing by down-regulating cell surface immune sensors. Secondly, immune cell dysfunction impairs their ability to execute anti-cancer functions. Radiotherapy, one of the cornerstones of cancer treatment, has the potential to enhance the immunogenicity of cancer cells and trigger an anti-tumor immune response. Inspired by this, we fabricate biofunctionalized liposome-like nanovesicles (BLNs) by exposing irradiated-cancer cells to ethanol, of which ethanol serves as a surfactant, inducing cancer cells pyroptosis-like cell death and facilitating nanovesicles shedding from cancer cell membrane. These BLNs are meticulously designed to disrupt both of the aforementioned mechanisms. On one hand, BLNs up-regulate the expression of calreticulin, an "eat me" signal on the surface of cancer cells, thus promoting macrophage phagocytosis of cancer cells. Additionally, BLNs are able to reprogram M2-like macrophages into an anti-cancer M1-like phenotype. Using a mouse model of malignant pleural effusion (MPE), an advanced-stage and immunotherapy-resistant cancer model, we demonstrate that BLNs significantly increase T cell infiltration and exhibit an ablative effect against MPE. When combined with PD-1 inhibitor (α-PD-1), we achieve a remarkable 63.6% cure rate (7 out of 11) among mice with MPE, while also inducing immunological memory effects. This work therefore introduces a unique strategy for overcoming immunotherapy resistance.

Irradiated tumour cell-derived microparticles upregulate MHC-I expression in cancer cells via DNA double-strand break repair pathway.

Radiotherapy (RT) is used for over 50 % of cancer patients and can promote adaptive immunity against tumour antigens. However, the underlying mechanisms remain unclear. Here, we discovered that RT induces the release of irradiated tumour cell-derived microparticles (RT-MPs), which significantly upregulate MHC-I expression on the membranes of non-irradiated cells, enhancing the recognition and killing of these cells by T cells. Mechanistically, RT-MPs induce DNA double-strand breaks (DSB) in tumour cells, activating the ATM/ATR/CHK1-mediated DNA repair signalling pathway, and upregulating MHC-I expression. Inhibition of ATM/ATR/CHK1 reversed RT-MP-induced upregulation of MHC-I. Furthermore, phosphorylation of STAT1/3 following the activation of ATM/ATR/CHK1 is indispensable for the DSB-dependent upregulation of MHC-I. Therefore, our findings reveal the role of RT-MP-induced DSBs and the subsequent DNA repair signalling pathway in MHC-I expression and provide mechanistic insights into the regulation of MHC-I expression after DSBs.

Clinical practice guidelines for prevention and treatment of postoperative gastrointestinal disorder with Integrated Traditional Chinese and Western Medicine (2023).

Postoperative gastrointestinal disorder (POGD) was a common complication after surgery under anesthesia. Strategies in combination with Traditional Chinese Medicine and Western medicine showed some distinct effects but standardized clinical practice guidelines were not available. Thus, a multidisciplinary expert team from various professional bodies including the Perioperative and Anesthesia Professional Committees of the Chinese Association of Integrative Medicine (CAIM), jointly with Gansu Province Clinical Research Center of Integrative Anesthesiology/Anesthesia and Pain Medical Center of Gansu Provincial Hospital of Traditional Chinese Medicine and WHO Collaborating Center for Guideline Implementation and Knowledge Translation/Chinese Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Center/Gansu Provincial Center for Medical Guideline Industry Technology/Evidence-based Medicine Center of Lanzhou University, was established to develop evidence-based guidelines. Clinical questions (7 background and 12 clinical questions) were identified through literature reviews and expert consensus meetings. Based on systematic reviews/meta-analyses, evidence quality was analyzed and the advantages and disadvantages of interventional measures were weighed with input from patients' preferences. Finally, 20 recommendations were developed through the Delphi-based consensus meetings. These recommendations included disease definitions, etiologies, pathogenesis, syndrome differentiation, diagnosis, and perioperative prevention and treatment.

Bacteria-Based Backpacks to Enhance Adoptive Macrophage Transfer against Solid Tumors.

Adoptive cell therapy has emerged as a promising approach for cancer treatment. However, the transfer of macrophages exhibits limited efficacy against solid tumors due to the dynamic cellular phenotypic shift from antitumor to protumor states within the immunosuppressive tumor microenvironment. In this study, a strategy of attaching bacteria to macrophages (Mø@bac) is reported that endows adoptively infused macrophages with durable stimulation by leveraging the intrinsic immunogenicity of bacteria. These attached bacteria, referred to as backpacks, are encapsulated with adhesive nanocoatings and can sustainably control the cellular phenotypes in vivo. Moreover, Mø@bac can repolarize endogenous tumor-associated macrophages, leading to a more robust immune response and thus reducing the tumor progression in a murine 4T1 cancer model without any side effects. This study utilizing bacteria as cellular backpacks opens a new avenue for the development of cell therapies.

A PD-L1-targeting Regulator for Metabolic Reprogramming to Enhance Glutamine Inhibition-Mediated Synergistic Antitumor Metabolic and Immune Therapy.

Inhibition of glutamine metabolism in tumor cells can cause metabolic compensation-mediated glycolysis enhancement and PD-L1 upregulation-induced immune evasion, significantly limiting the therapeutic efficacy of glutamine inhibitors. Here, inspired by the specific binding of receptor and ligand, a PD-L1-targeting metabolism and immune regulator (PMIR) are constructed by decorating the glutaminase inhibitor (BPTES)-loading zeolitic imidazolate framework (ZIF) with PD-L1-targeting peptides for regulating the metabolism within the tumor microenvironment (TME) to improve immunotherapy. At tumor sites, PMIR inhibits glutamine metabolism of tumor cells for elevating glutamine levels within the TME to improve the function of immune cells. Ingeniously, the accompanying PD-L1 upregulation on tumor cells causes self-amplifying accumulation of PMIR through PD-L1 targeting, while also blocking PD-L1, which has the effects of converting enemies into friends. Meanwhile, PMIR exactly offsets the compensatory glycolysis, while disrupting the redox homeostasis in tumor cells via the cooperation of components of the ZIF and BPTES. These together cause immunogenic cell death of tumor cells and relieve PD-L1-mediated immune evasion, further reshaping the immunosuppressive TME and evoking robust immune responses to effectively suppress bilateral tumor progression and metastasis. This work proposes a rational strategy to surmount the obstacles in glutamine inhibition for boosting existing clinical treatments.

Dendritic Cell-Based In Situ Nanovaccine for Reprogramming Lipid Metabolism to Boost Tumor Immunotherapy.

Cancer vaccines have been considered to be an alternative therapeutic strategy for tumor therapy in the past decade. However, the popularity and efficacy of cancer vaccines were hampered by tumor antigen heterogeneity and the impaired function of cross-presentation in the tumor-infiltrating dendritic cells (TIDCs). To overcome these challenges, we engineered an in situ nanovaccine (named as TPOP) based on lipid metabolism-regulating and innate immune-stimulated nanoparticles. TPOP could capture tumor antigens and induce specific recognition by TIDCs to be taken up. Meanwhile, TPOP could manipulate TIDC lipid metabolism and inhibit de novo synthesis of fatty acids, thus improving the ability of TIDCs to cross-present by reducing their lipid accumulation. Significantly, intratumoral injection of TPOP combined with pretreatment with doxorubicin showed a considerable therapeutic effect in the subcutaneous mouse colorectal cancer model and melanoma model. Moreover, in combination with immune checkpoint inhibitors, such TPOP could markedly inhibit the growth of distant tumors by systemic antitumor immune responses. This work provides a safe and promising strategy for improving the function of immune cells by manipulating their metabolism and activating the immune system effectively for in situ cancer vaccines.

Favorable response to surufatinib in a patient with necrolytic migratory erythema: A case report.

Necrolytic migratory erythema (NME) is usually associated with paraneoplastic syndrome caused by functional pancreatic neuroendocrine tumor (PNET). Accurate diagnosis and effective treatment of NET-related NME is challenging due to its rarity and lack of typical clinical symptoms and specific pathological manifestations. Here we report a rare case of PNET with NME as the initial manifestation. 68Ga-DOTA-TATE PET/MR was used to detect the primary pancreatic and metastatic liver tumors. Finally, the patient was diagnosed as PNET via liver biopsy. After four cycles of standard capecitabine plus temozolomide chemotherapy combined with long-acting octreotide, the patient's skin lesions on both lower extremities improved only slightly, while tumors remained stable and unchanged in size. Then the patient was treated with surufatinib. Two months later, the skin lesions healed completely, and tumors responded significantly. This rare case suggests that surufatinib may be a promising therapy for patients with PNET-associated NME.

Therapeutic role of Wuda granule in gastrointestinal motility disorder through promoting gastrointestinal motility and decreasing inflammatory level.

Introduction: Previous studies indicated that Wuda Granule (WDG) has been applied in the treatment of gastrointestinal motility disorder (GMD), but the effect and underlying mechanisms is yet to be elucidated. This study aimed to explore the mechanism and pharmacological effect of WDG for GMD via network analysis, verification of animal experiments and clinical experiments. Methods: The chemical components of WDG were identified from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP, http://lsp.nwu.edu.cn/index.php), and the Encyclopedia of Traditional Chinese Medicine (ETCM, http://www.tcmip.cn/ETCM/index.php/Home/Index/) according to oral bioavailability (OB) ≥ 20% and drug-likeness (DL) ≥ 0.10. The targets of WDG compounds were retrieved from the Swiss Target Prediction database (http://www.swisstargetprediction.ch/) and targets related to GMD were retrieved from GeneCards database (https://www.genecards.org/). Network analysis were performed to screen the key active compounds of WDG and its hub targets. Then the pharmacological effect of WDG were verified via vivo experiments in rats and clinical experiments. Results: The results showed that 117 effective active compounds of WDG were screened and 494 targets of WDG compounds targeting GMD were selected. These targets were involved in the biological process of inflammatory regulation and the regulation of gastrointestinal motility. The mechanism was mainly involved in the regulation of PI3K-Akt signaling pathway and Rap1 signaling pathway. In addition, molecular docking analysis suggested that eight key active compounds of WDG may be mainly responsible for the effect of WDG on GMD by targeting HARS, AKT, and PIK3CA, respectively. Animal experiments and clinical trials both suggested that WDG could exert therapeutical effect on GMD via inhibiting inflammation and promoting gastrointestinal motility, it could also improve digestive function of patients with laparoscopic colorectal cancer after surgery. Conclusion: This study was the first to demonstrate that WDG improved GMD mainly via inhibiting inflammatory level and promoting gastrointestinal motility, providing new insights for the understanding of WDG for GMD, inspiration for future research and reference for clinical strategy in terms of the treatment of GMD.

Engineering metal-based hydrogel-mediated tertiary lymphoid structure formation via activation of the STING pathway for enhanced immunotherapy.

Tertiary lymphoid structures (TLSs) primarily constructed by multiple immune cells can effectively enhance tumor immune responses, but expediting the formation of TLSs is still an enormous challenge. Herein, a stimulator of interferon gene (STING)-activating hydrogel (ZCCG) was elaborately developed by coordinating Zn2+ with 4,5-imidazole dicarboxylic acid, and simultaneously integrating chitosan (a stimulant of STING pathway activation) and CpG (an agonist of toll-like receptor 9, TLR9) for initiating and activating cGAS-STING and TLR9 pathway-mediated immunotherapy. Moreover, the dual-pathway activation could effectively enhance the infiltration of immune cells and the expression of lymphocyte-recruiting chemokines in the tumor microenvironment (TME), thereby promoting the formation of TLSs and further strengthening tumoricidal immunity. Local administration of the hydrogel could prime systemic immune responses and long-term immune memory and improve the therapeutic effects of programmed death-1 antibody (αPD-1) to inhibit tumor progression, metastasis and recurrence. The engineered hydrogel lays the foundation for tumor immunotherapy strategies based on the enhanced formation of TLSs via the activation of the cGAS-STING and TLR9 pathways.

Proteomic analysis reveals that Polygonatum cyrtonema Hua polysaccharide ameliorates mice muscle atrophy in chemotherapy-induced cachexia.

Polygonatum cyrtonema Hua polysaccharide (PCP) is the main bioactive compound derived from the herb Polygonati Rhizoma, known for its anti-fatigue, antioxidant, immunomodulatory, and anti-inflammatory properties. However, its effectiveness on alleviating chemotherapy-induced muscle atrophy has been unclear. In this study, we utilized proteomic analysis to investigate the effects and mechanisms of PCP on gemcitabine plus cisplatin (GC) induced muscle atrophy in mice. Quality control analysis revealed that the functional PCP, rich in glucose, is a heterogeneous polysaccharide comprised of nine monosaccharides. PCP (64 mg/kg) significantly alleviated body muscle, organ weight loss, and muscle fiber atrophy in chemotherapy-induced cachectic mice. Moreover, PCP suppressed the decrease in serum immunoglobulin levels and the increase in pro-inflammatory factor interleukin-6 (IL-6). Proteomic analysis demonstrated that PCP contributed to the homeostasis of protein metabolism in gastrocnemius muscle. Diacylglycerol kinase (DGKζ) and cathepsin L (CTSL) were identified as primary PCP targets. Furthermore, the IL-6/STAT3/CTSL and DGKζ/FoxO/Atrogin1 signaling pathways were validated. Our findings suggest that PCP exerts an anti-atrophy effect on chemotherapy-induced muscle atrophy by regulating the autophagy-lysosome and ubiquitin-proteasome systems.

Radiated tumor cell-derived microparticles effectively kill stem-like tumor cells by increasing reactive oxygen species.

Stem-like tumor cells (SLTCs) are thought to be the cellular entity responsible for clinical recurrence and subsequent metastasis. Inhibiting or killing SLTCs can effectively reduce recurrence and metastasis, yet little has been done to clear SLTCs because they are usually resistant to chemotherapy, radiotherapy, and even immunotherapy. In this study, we established SLTCs by low-serum culture and confirmed that the low-serum-cultured tumor cells were in a quiescent state and resistant to chemotherapy, showing features of SLTCs, consistent with the reported data. We demonstrated that SLTCs had high levels of reactive oxygen species (ROS). Based on the finding that radiated tumor cell-derived microparticles (RT-MPs) contained ROS, we used RT-MPs to kill SLTCs. We found that RT-MPs could further increase ROS levels and kill SLTCs in vivo and in vitro partially by ROS carried by the RT-MPs themselves, providing a new method for eliminating SLTCs.

Nomograms incorporating primary tumor response at mid-radiotherapy to predict survival in locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND: A nomogram that incorporates tumor response at mid-radiotherapy (mid-RT) to predict the prognosis of locoregionally advanced nasopharyngeal carcinoma (LA-NPC) has not been established. METHODS: This study retrospectively reviewed 583 patients with LA-NPC who underwent magnetic resonance imaging scans at mid-RT (the fourth week of RT) between 2015 and 2019. RESULTS: Primary tumor (PT) response at mid-RT was found to predict disease-free survival (DFS) and overall survival (OS). Independent factors from multivariable analysis to predict DFS and OS were assembled into nomograms with (nomograms Amid-RT and Bmid-RT ) or without (nomograms Abaseline and Bbaseline ) PT response. Internal validation revealed good performance of these nomograms in discrimination: C-statistics = 0.761 for nomogram Amid-RT and 0.809 for nomogram Bmid-RT , which showed better discrimination performance than (C-statistics: 0.755) nomogram Abaseline and (C-statistics: 0.798) nomogram Bbaseline (Z-statistic = 2.476, p < 0.05; Z-statistic = 1.971, p < 0.05). CONCLUSION: The nomograms based on PT response at mid-RT showed favorable predictive accuracy for DFS and OS in patients with LA-NPC.

An inorganic-organic-polymeric nanovehicle for targeting delivery of doxorubicin: Rational assembly, pH-stimulus release, and dual hyperthermia/chemotherapy of hepatocellular carcinoma.

Efficiently synergistic therapy of hepatocellular carcinoma (HCC) by chemotherapeutic drug and photothermal agent remains a considerable challenge. Here, we report a nanodrug that integrates specific hepatoma-targeted delivery, pH-triggered drug release, and cooperative photothermal-chemotherapy function. By grafting the easily self-assembled CuS@polydopamine (CuS@PDA) nanocapsulation with polyacrylic acid (PAA), an inorganic-organic-polymeric hybrid nanovehicle was developed as a dual photothermal agent and carrier for loading antitumor drug-doxorubicin (DOX) through electrostatic adsorption and chemical linking antibody against GPC3 commonly overexpressed in HCC, resulting in the nanodrug, CuS@PDA/PAA/DOX/GPC3. The multifunctional nanovehicle had excellent biocompatibility, stability, and high photothermal conversion efficiency, due to the rationally designed binary CuS@PDA photothermal agent. The 72-h accumulative drug release in pH 5.5 tumor microenvironment can reach up to 84%, far higher than 15% measured in pH 7.4 condition. Notably, in contrast to the merely 20% survival rate of H9c2 and HL-7702 cells exposed to free DOX, their viabilities in the nanodrug circumstance can maintain 54% and 66%, respectively, suggesting the abated toxicity to the normal cell lines. When exposed to the hepatoma-targeting nanodrug, the viability of HepG2 cells was found to be 36%, which further drastically declined to 10% plus 808-nm NIR irradiation. Moreover, the nanodrug is potent to cause tumor ablation in HCC-modeled mice, and the therapeutic efficacy can be greatly enhanced under NIR stimulus. Histology analyses reveal that the nanodrug can effectively alleviate the chemical damage to heart and liver, as compared to free DOX. This work thus offers a facile strategy for design of targeting anti-HCC nanodrug toward combined photothermal-chemotherapy.

Survival benefit of thoracic radiotherapy plus EGFR-TKIs in patients with non-oligometastatic advanced non-small-cell lung cancer: a single-center retrospective study.

Objectives: The study aims to evaluate the efficacy and safety of thoracic radiotherapy in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-treated patients with stage IV non-small-cell lung cancer (NSCLC). Methods: Patients with non-oligometastatic NSCLC harboring EGFR mutations were recruited. All patients received the first-generation TKI treatment with or without radiotherapy. The irradiated sites included primary and/or metastatic lesions. Of all the patients who underwent thoracic radiotherapy, some received radiotherapy before EGFR-TKI resistance, others received radiotherapy after progressive disease. Results: No statistically significant difference was observed in progression-free survival (PFS) (median 14.7 versus 11.2 months, p = 0.075) or overall survival (OS) (median 29.6 versus 40.6 months, p = 0.116) between patients treated with EGFR-TKIs alone and those with additional radiotherapy to any sites. However, EGFR inhibitors with thoracic radiation significantly improved OS (median 47.0 versus 31.0 months, p < 0.001) but not PFS (median 13.9 versus 11.9 months, p = 0.124). Moreover, longer PFS (median 18.3 versus 8.5 months, p < 0.001) was achieved in the preemptive thoracic radiation cohort than in the delayed thoracic radiation cohort. However, OS was similar between the two cohorts (median 40.6 versus 52.6 months, p = 0.124). The lower incidence rate of grade 1-2 pneumonitis occurred in preemptive radiation cohort (29.8% versus 75.8%, p < 0.001). Conclusion: Non-oligometastatic NSCLC patients with EGFR mutations benefited from thoracic radiotherapy while using EGFR inhibitors. Preemptive thoracic radiotherapy could be a competitive first-line therapeutic option due to superior PFS and favorable safety.

Transoral Endoscopic Thyroidectomy by Vestibular Approach for Papillary Thyroid Carcinoma with Tumor Size ≥2 cm.

Background: The transoral endoscopic thyroidectomy by vestibular approach (TOETVA) has been developed for papillary thyroid carcinoma (PTC) treatment with satisfactory results. However, there were few malignant thyroid nodules ≥2 cm in previous studies of TOETVA. Therefore, we conducted this study to evaluate the results of treatment by TOETVA for PTC with tumor size ≥2 cm. Materials and Methods: The clinical characteristics and surgical outcomes of 10 PTC patients with tumor size ≥2 cm who underwent TOETVA in our center from June 2018 to August 2021 were, respectively, reviewed. Results: All 10 included PTC patients successfully underwent TOETVA and the mean tumor size was 2.5 ± 0.5 cm. The mean number lymph nodes dissected was 9.6 ± 2.9, and 3.1 ± 3.3 positive lymph nodes were discovered. Postoperatively, transient hypoparathyroidism was recorded in 2 patients (20%), transient recurrent laryngeal nerve injury was noted in 1 patient (10%), transient superior laryngeal nerve injury was noted in 1 patient (10%), and numb chin was identified in 1 patient (10%). The postoperative complications aforementioned recovered within 6 months. During a median follow-up of 23.8 ± 13.1 months, no other complications or tumor recurrence were found. Conclusions: TOETVA is feasible for PTC patients with tumor size ≥2 cm and satisfactory short-term surgical outcomes have achieved in this study. We suggested that experienced surgeons can gradually expand the indications for TOETVA.

Radiotherapy plus cetuximab or cisplatin in head and neck squamous cell carcinoma: an updated systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The present meta-analysis was updated with randomized controlled trials (RCTs) to revaluate the efficacy and safety of cetuximab vs. cisplatin combined with radiotherapy in patients of head and neck squamous cell carcinoma (HNSCC). METHODS: A meta-analysis containing RCTs that compared the efficacy or toxicity of cetuximab and cisplatin in HNSCC patients was conducted. RESULTS: Seven RCTs were included in the final analysis. The patients treated by cetuximab plus radiotherapy showed an inferior overall survival (OS) and locoregional control (LRC) compared to cisplatin plus radiotherapy. The tendency of progression-free survival (PFS) was in agreement with OS and LRC. Subgroup analysis showed that cetuximab had poorer OS relative to cisplatin in the absence of induction chemotherapy. The profile of severe adverse events (SAEs) varied between the two groups, no significant difference in total SAEs was shown for the two arms. DISCUSSION: Cetuximab combined with radiotherapy shows significantly reduced therapeutic efficacy compared to cisplatin plus radiotherapy in HNSCC patients.

A novel hybrid approach for "Scarless" (at the neck) lateral neck dissection for papillary thyroid carcinoma: A case series and literature review.

Lateral neck dissection (LND) is a necessary treatment for thyroid cancer with lateral lymph node metastasis. However, the defect created during open surgery leaves a visible scar on the neck. With advancements in surgical technology, many robotic and endoscopic surgical techniques have been reported as alternatives to open surgery. In this study, we present a case series demonstrating the successful application of a novel hybrid approach for endoscopic LND and a review of different surgical approaches for "scarless" (at the neck) LND. We performed endoscopic LND via a combined chest and transoral approach in 24 patients between January 2021 and March 2022. The surgery was completed successfully in all patients with an average operation time of 298.1 ± 72.9 min. The numbers of positive/retrieved lymph nodes at levels II, III-IV, and VI were 0.7 ± 0.9/8.4 ± 4.1, 3.6 ± 2.7/19.5 ± 6.8, and 4.9 ± 3.9/10.3 ± 4.5, respectively. Complications included transient hypoparathyroidism in 10 patients, transient recurrent laryngeal nerve injury in 1 patient, internal jugular vein (IJN) injury in 1 patient, IJN sacrifice due to cancer invasion in 1 patient, and chyle leak in 1 patient, and no cases of tumor recurrence were observed during follow-up. The present case series indicates that the combined chest and transoral approach is feasible and effective for performing LND. Our review of different approaches for "scarless" (at the neck) LND identified advantages and disadvantages for all techniques. Our novel approach has unique advantages, and thus, it can provide an ideal surgical procedure for specific papillary thyroid carcinoma patients.

Molecular characteristics of pediatric nasopharyngeal carcinoma using whole-exome sequencing.

OBJECTIVES: While a number of genetic and epigenetic events contributing to adult nasopharyngeal carcinomas (aNPC) development has been established, the scarcity of pediatric nasopharyngeal carcinoma (pNPC) hinders the understanding of the biology of the disease and rational treatment approach. We aim to identify the molecular characteristics of pNPC. MATERIALS AND METHODS: pNPC primary tumors with paired blood samples were collected and sequenced using whole-exome sequencing. Samples were collected from four tertiary academic medical centers in China. A total of 30 patients (25 male and 5 female) with pathologically confirmed NPC under the age of 20 were enrolled. RESULTS: Several genes such as C9orf84 (20 %), ZFHX4 (16.7 %), ZC3H6 (16.7 %), RBM38 (16.7 %) were frequently mutated in pNPC. Copy number analysis revealed highly recurring gain/amplification of the HLA class II genes at 6p21.32 (63.3 %) and losses of TOLLIP at 11p15.5 (20 %). Recurrent NUTM1 (16.7 %) fusion variants were found for the first time with pNPC. We also investigated germline genomic signatures and showed 8 of 30 (26.7 %) of the pNPC patients carrying germline pathogenic and/or likely pathogenic variants in known cancer-predisposing genes. Multi-dimensional comparison suggested that pNPC might exhibit distinct genomic profile compared to aNPC. In addition, pNPC exhibited significantly elevated level of PD-L1 expression than aNPC (percent of patients with >50 % PD-L1 expression: 92.0 % vs 32.1 %), suggesting high possibility of benefit from immunotherapy. CONCLUSION: Our results provide the first insight into the molecular basis of pNPC, and might offer novel targets and therapeutic approaches such as immunotherapy for this rare disease.

Cancer stem cell antigen nanodisc cocktail elicits anti-tumor immune responses in melanoma.

One of the major reasons for poor cancer outcomes is the existence of cancer stem cells (CSCs). CSCs are a small subpopulation of tumor cells that can self-renew, differentiate into the majority of tumor cells, and maintain tumorigenicity. As CSCs are resistant to traditional chemotherapy and radiation, they contribute to metastasis and relapse. Thus, new approaches are needed to target and eliminate CSCs. Here, we sought to target and reduce the frequency of CSCs in melanoma by therapeutic vaccination against CSC-associated transcription factors, such as Sox2 and Nanog, and aldehyde dehydrogenase (ALDH). Toward this goal, we have identified novel immunogenic peptide epitopes derived from CSC-associated Sox2 and Nanog and synthesized synthetic high-density lipoprotein (sHDL) nanodisc vaccine formulated with Sox2, Nanog, and ALDH antigen peptides together with CpG, a Toll-like receptor 9 agonist. Vaccination with nanodiscs containing six CSC antigen peptides elicited robust T cell responses against CSC-associated antigens and promoted intratumoral infiltration of CD8+ T cells, while reducing the frequency of CSCs and CD4+ regulatory T cells within melanoma tumors. Nanodisc vaccination effectively reduced tumor growth and significantly extended animal survival without toxicity toward normal stem cells. Overall, our therapeutic strategy against CSCs represents a cost-effective, safe, and versatile approach that may be applied to melanoma and other cancer types, as well as serve as a critical component in combined therapies to target and eliminate CSCs.

Emerging concepts regarding pro- and anti tumor properties of B cells in tumor immunity.

Controversial views regarding the roles of B cells in tumor immunity have existed for several decades. However, more recent studies have focused on its positive properties in antitumor immunity. Many studies have demonstrated a close association of the higher density of intratumoral B cells with favorable outcomes in cancer patients. B cells can interact with T cells as well as follicular dendritic cells within tertiary lymphoid structures, where they undergo a series of biological events, including clonal expansion, somatic hypermutation, class switching, and tumor-specific antibody production, which may trigger antitumor humoral responses. After activation, B cells can function as effector cells via direct tumor-killing, antigen-presenting activity, and production of tumor-specific antibodies. At the other extreme, B cells can obtain inhibitory functions by relevant stimuli, converting to regulatory B cells, which serve as an immunosuppressive arm to tumor immunity. Here we summarize our current understanding of the bipolar properties of B cells within the tumor immune microenvironment and propose potential B cell-based immunotherapeutic strategies, which may help promote cancer immunotherapy.