Treatment of primary nasal tuberculosis with anti-tumor necrosis factor immunotherapy:A case report

BACKGROUND Primary nasal tuberculosis(TB)is a rare form of extrapulmonary TB,particularly in patients receiving anti-tumor necrosis factor(TNF)immunotherapy.As a result,its diagnosis remains challenging.CASE SUMMARY A 58-year-old male patient presented to the ear,nose,and throat department with right-sided nasal obstruction and bloody discharge for 1 month.He was diagnosed with psoriatic arthritis and received anti-TNF immunotherapy for 3 years prior to presentation.Biopsy findings revealed chronic granulomatous inammation and a few acid-fast bacilli,suggestive of primary nasal TB.He was referred to our TB management department for treatment with oral anti-TB agents.After 9 months,the nasal lesions had disappeared.No recurrence was noted during follow-up.CONCLUSION The diagnosis of primary nasal TB should be considered in patients receiving TNF antagonists who exhibit thickening and crusting of the nasal septum mucosa or inferior turbinate,particularly when pathological findings suggest granulomatous inflammation.

Spatiotemporal transformable nano-assembly for on-demand drug delivery to enhance anti-tumor immunotherapy

Induction of tumor cell senescence has become a promising strategy for anti-tumor immunotherapy,but fibrotic matrix severely blocks senescence inducers penetration and immune cells infiltration.Herein,we designed a cancer-associated fibroblasts(CAFs)triggered structure-transformable nano-assembly(HSD-P@V),which can directionally deliver valsartan(Val,CAFs regulator)and doxorubicin(DOX,senescence inducer)to the specific targets.In detail,DOX is conjugated with hyaluronic acid(HA)via diselenide bonds(Se-Se)to form HSD micelles,while CAFs-sensitive peptide is grafted onto the HSD to form a hydrophilic polymer,which is coated on Val nanocrystals(VNs)surface for improving the stability and achieving responsive release.Once arriving at tumor microenvironment and touching CAFs,HSD-P@V disintegrates into VNs and HSD micelles due to sensitive peptide detachment.VNs can degrade the extracellularmatrix,leading to the enhanced penetration of HSD.HSD targets tumor cells,releases DOX to induce senescence,and recruits effector immune cells.Furthermore,senescent cells are cleared by the recruited immune cells to finish the integrated anti-tumor therapy.In vitro and in vivo results show that the nanoassembly remarkably inhibits tumor growth as well as lungmetastasis,and extends tumorbearing mice survival.This work provides a promising paradigm of programmed delivering multi-site nanomedicine for cancer immunotherapy.

Thermal ablation and immunotherapy for hepatocellular carcinoma:Recent advances and future directions

Hepatocellular carcinoma(HCC)is one of most common cancers that cause death in the world.Thermal ablation(TA)is an important alternative treatment method for HCC patients who are not appropriate for surgery or liver transplantation.Particularly for small and early HCCs,TA can be considered as the first-line curative treatment.However,local and distant recurrence rates are still high even though the TA equipment and technology develop rapidly.Immunotherapy is a novel systemic treatment method to enhance the anti-tumor immune response of HCC patients,which has the potential to reduce the tumor recurrence and metastasis.The combination of local TA and systemic immunotherapy for HCCs may be an ideal treatment for enhancing the efficacy of TA and controlling the recurrence.Herein we summarize the latest progress in TA,immunotherapy,and their combination for the treatment of patients with HCC and discuss the limitations and future research directions of the combined therapy.

ANTI-TUMOR RESPONSES INDUCED BY LASER IRRADIATION AND IMMUNOLOGICAL STIMULATION USING A MOUSE MAMMARY TUMOR MODEL

Anti-tunor immunological response induced by local intervention is ideal for treatment of metastatic tumors.Laser immunot herapy was developed to synergize photot hermal interaction with immunological stimulation for cancer treatment.Using an infrared laser,indocyanine green(ICG,as a light abeorbing agent),and glycated chitosan(GC,as an immunostimulant),.laser imm unot herapy has resulted in tumor suppression and anti-tumor responses in pre-clinical as well as clinical studies.To further understand the mechanism of laser immunotherapy,the efects of laser and GC treatment without specifc enhancement of laser absorption were studied.Passive adoptive immunity transfer was perfomed using splenocytes as immune cells.Spleen cells harvested from tumor-bearing mice treated by laser+GC provided 60%immunity in naive recipients.Furthermore,cytotoxicity and TNF-ar secretion by splenocytes from treated mice also indicated that laser+GC induced immunity was tumor-specific.The high level of infiltrating T cells in tumors after laser+GC treatment furt her confirned a specific anti-tumor immune response.Therefore,laser+GC could prove to be a promisi ng selective local trea tment modality that induces a systemic anti-tumor response,with appropriate laser parameters and GC doses.

Anti-tumor response induced by immunologically modified carbon nanotubes and laser irradiation using rat mammary tumor model

The ideal treatment modality for metastatic cancer would be a local treatment that can destroy primary tumors while inducing an effective systemic anti-tumor response.To this end,we de-veloped laser immunotherapy,combining photothermal laser application with an immunoadju-vant for the treatment of metastatic cancer.Additionally,to enhance the selective photothermal effect,we integrated light-absorbing nanomaterials into this innovative treatment.Specifically,we developed an immunologically modified carbon nanotube combining single-walled carbon nanotubes(SWNTs)with the immunoadjuvant glycated chitosan(GC).To determine the ef-fectiveness of laser iradiation,a series of experiments were performed using two different irra-diation durations-5 and 10 min.Rats were inoculated with DMBA-4 cancer cells,a metastatic cancer cell line.The treatment group of rats receiving laser irradiation for 10 min had a 50%long-term survival rate without residual primary or metastatic tumnors.The treatment group of rats receiving laser irradiation for 5 min had no long-term survivors;all rats died with multiple metastases at several distant sites.Therefore,Laser+SWNT-GC treatment with 10 min of laser irradiation proved to be efective at reducing tumor size and inducing long-term anti-tumor immunity.

Study on the Anti-tumor Mechanism of Immunological Checkpoint Inhibitor PD-1

In recent years,the research of programmed death factor-1(PD-1)and its ligand(PD-L1)has made a great breakthrough in tumor therapy,and it is expected to change the clinical treatment manner of anti-tumor.In this paper,the role and mechanism of PD-1 inhibitors in anti-tumor are reviewed,thereby promoting their clinical application in anti-tumor immunotherapy.

Blockading a new NSCLC immunosuppressive target by pluripotent autologous tumor vaccines magnifies sequential immunotherapy

The presence of multiple immunosuppressive targets and insufficient activation and infiltration of cytotoxic T lymphocytes(CTLs)allow tumor cells to escape immune surveillance and disable anti-PD-1/PD-L1 immunotherapy.Nanobiotechnology-engineered autologous tumor vaccines(ATVs)that were camouflaged by tumor cell membrane(TCM)were designed to activate and facilitate CTLs infiltration for killing the unprotected lung tumor cells,consequently realizing the sequential immunotherapy.PDE5 was firstly screened out as a new immunosuppressive target of lung cancer in clinical practice.Immediately afterwards,phosphodiesterase-5(PDE5)and programmed cell death 1 ligand 1(PD-L1)dual-target co-inhibition was proposed to unfreeze the immunosuppressive microenvironment of NSCLC.Systematic studies validated that this ATVs-unlocked sequential immunotherapy after co-encapsulating PDE5 inhibitor and NO donor(i.e.,L-arginine)exerted robust anti-tumor effects through increasing inducible nitric oxide synthase(iNOS)expression,blockading PDE5 pathway and activating systematic immune responses,which synergistically eradicated local and abscopal lung cancers in either orthotopic or subcutaneous models.The pluripotent ATVs that enable PDE5 inhibition and sequential immunotherapy provide a new avenue to mitigate immunosuppressive microenvironment and magnify anti-PD-1/PD-L1 immunotherapy.

结直肠癌术后辅助化疗序贯免疫治疗的应用效果

目的分析结直肠癌术后辅助化疗序贯免疫治疗的应用效果。方法回顾性分析2018年12月至2020年12月本院收治的60例结直肠癌术后患者的临床资料,按照治疗方式不同分为实验组和对照组,各30例。对照组采取术后辅助化疗治疗,实验组采取术后辅助化疗序贯免疫治疗,比较两组免疫功能、毒副反应情况、生命质量。结果治疗前,两组CD8^(+)、CD4^(+)、B细胞、自然杀伤样T(NKT)细胞和自然杀伤(NK)细胞水平与CD4^(+)/CD8^(+)比较差异无统计学意义;治疗后,实验组CD8^(+)、B细胞、NKT细胞水平均低于对照组,CD4^(+)、NK细胞水平及CD4^(+)/CD8^(+)均高于对照组,差异有统计学意义(P<0.05)。实验组毒副反应发生率为16.67%,明显低于对照组的46.67%,差异有统计学意义(P<0.05)。实验组生理职能、生理功能、活力、精神健康、情感职能、社会功能、躯体疼痛、总体健康评分均高于对照组,差异有统计学意义(P<0.05)。结论结直肠癌术后辅助化疗序贯免疫治疗的效果理想,可明显改善患者免疫功能与生命质量,且基本不会引起毒副反应,值得临床推广应用。

序贯免疫治疗对乳腺癌患者血清雌激素及Treg细胞与TGF-β1、IL-10的影响

目的探讨序贯免疫治疗对乳腺癌患者血清雌激素(E2)及Treg细胞与TGF-β1、IL-10的影响及其临床意义。方法选取我院肿瘤科收治的乳腺癌患者100例,根据治疗方案不同分为对照组和试验组。比较两组患者血清E2及Treg细胞、CD4+、CD8+、TGF-β1、IFN-γ及IL-4、IL-6、IL-10等指标变化的关系。结果序贯免疫治疗可明显降低雌激素及TGF、Treg细胞水平,增强DC-CIK细胞对肿瘤细胞的杀伤作用,表现为试验组患者E2、TGF-β1、Treg细胞及Th1、Th2细胞因子水平明显低于对照组(P<0.05),IFN-γ及CD4+、CD8+水平明显高于对照组(P<0.05)。结论序贯免疫治疗可增强机体DC-CIK细胞对肿瘤细胞的杀伤作用,控制E2对肿瘤细胞活性刺激,降低TGF-β1及Treg细胞比率,抑制自身免疫的进行,提高T淋巴细胞等免疫细胞活性,较传统治疗方案耐药性低、副作用小、临床疗效理想,可作为临床治疗的有效方案,并具有重要意义。

特应性皮炎的治疗

特应性皮炎(AD)是一种以瘙痒和湿疹为主要特征的慢性炎症疾病,严重影响患者的生活质量。由于病因和发病机制至今尚未完全明确,其治疗在临床上仍然是一个挑战。大多数患者可通过避免激发因素、基础皮肤护理和外用抗炎药得到较好的疗效,少部分患者皮损广泛且对常规治疗抵抗,需要系统药物治疗。由于患者的病情严重程度、合并的病变及发病年龄变异很大,在治疗上应遵循按照疾病严重程度进行个体化的阶梯治疗方案的原则。在选择系统治疗时,在考虑其治疗收益的同时应考虑其安全性和副反应。

GEMSTONE⁃301:同步/序贯放化疗后舒格利单抗巩固治疗可提高不可手术的Ⅲ期非小细胞肺癌患者的生存

1文献来源Wu Y,Zhou Q,Chen M,et al.LBA43⁃GEMSTONE⁃301:A randomized,double⁃blind,placebo⁃controlled,phase 3 study of sugemalimab in patients with unresectable stageⅢnon⁃small cell lung cancer(NSCLC)who had not progressed after concurrent or sequential chemoradiotherapy(CRT)[J].Ann Oncol,2021,32(5S):S1283-S1346。

The crosstalk between ferroptosis and anti-tumor immunity in the tumor microenvironment:molecular mechanisms and therapeutic controversy

The advent of immunotherapy has significantly reshaped the landscape of cancer treatment,greatly enhancing therapeutic outcomes for multiple types of cancer.However,only a small subset of individuals respond to it,underscoring the urgent need for new methods to improve its response rate.Ferroptosis,a recently discovered form of programmed cell death,has emerged as a promising approach for anti-tumor therapy,with targeting ferroptosis to kill tumors seen as a potentially effective strategy.Numerous studies suggest that inducing ferroptosis can synergistically enhance the effects of immunotherapy,paving the way for a promising combined treatment method in the future.Nevertheless,recent research has raised concerns about the potential negative impacts on anti-tumor immunity as a consequence of inducing ferroptosis,leading to conflicting views within the scientific community about the interplay between ferroptosis and anti-tumor immunity,thereby underscoring the necessity of a comprehensive review of the existing literature on this relationship.Previous reviews on ferroptosis have touched on related content,many focusing primarily on the promoting role of ferroptosis on anti-tumor immunity while overlooking recent evidence on the inhibitory effects of ferroptosis on immunity.Others have concentrated solely on discussing related content either from the perspective of cancer cells and ferroptosis or from immune cells and ferroptosis.Given that both cancer cells and immune cells exist in the tumor microenvironment,a one-sided discussion cannot comprehensively summarize this topic.Therefore,from the perspectives of both tumor cells and tumor-infiltrating immune cells,we systematically summarize the current conflicting views on the interplay between ferroptosis and anti-tumor immunity,intending to provide potential explanations and identify the work needed to establish a translational basis for combined ferroptosis-targeted therapy and immunotherapy in treating tumors.

A Rare Case of Small Bowel Intussusception Due to Metastatic Malignant Melanoma

The small intestine is sometimes metastasized by malignant melanoma. While small intestinal involvement is asymptomatic or usually nonspecific, intussusception causing intestinal obstruction is very rare. Herein we report the case of a 68-year-old man with small bowel intussusception due to metastatic malignant melanoma. Although he has been comprehensively treated with surgery, radiation, and immunotherapies, the disease rapidly progressed and consequently severe life-threatening intussusception developed on the small bowel. Because surgical resection of the obstructive melanoma lesions was successful, his quality of life was dramatically improved followed by the resumption of treatment with anti-PD-1. Several effective treatments for metastatic melanoma, including immune checkpoint inhibitors and targeted therapy, have been developed within the past decade. However, given the present case, surgical approaches to symptomatic metastatic melanoma lesions should still be considered as a treatment option for improving not only patients’ critical condition but also their survival.

B7S1, a novel candidate for anti-tumor checkpoint blockade immunotherapy

Antigen-specific CD8＋T cells play a critical role in eradicating transformed or virally infected cells. Upon recognition of cancerous or viral originated peptides, presented by antigen-presenting cells （APCs） in the form of peptide-MHC class I complex, CD8＋T cells become activated, rapidly and extensively proliferate and differentiate into functionally competent effector cells. Following successfully and timely clearing transformed or virally infected cells, the majority of effector CD8＋Tcells die of apoptosis. Concomitantly a small fraction （around 5%-10%） of effector CD8＋T cells survive and progressively differentiate into long-lived and self-renewable memory CD8＋T cells.

Targeting neuropilin-1 interactions is a promising anti-tumor strategy

Neuropilins(NRP1 and NRP2)are multifunctional receptor proteins that are involved in nerve,blood vessel,and tumor development.NRP1 was first found to be expressed in neurons,but subsequent studies have demonstrated its surface expression in cells from the endothelium and lymph nodes.NRP1 has been demonstrated to be involved in the occurrence and development of a variety of cancers.NRP1 interacts with various cytokines,such as vascular endothelial growth factor family and its receptor and transforming growth factor p i and its receptor,to affect tumor angiogenesis,tumor proliferation,and migration.In addition,NRP1+regulatory T cells(Tregs)play an inhibitory role in tumor immunity.High numbers of NRP1+Tregs were associated with cancer prognosis.Targeting NRP1 has shown promise,and antagonists against NRP1 have had therapeutic efficacy in preliminary clinical studies.NRP1 treatment modalities using nanomaterials,targeted drugs,oncolytic viruses,and radio-chemotherapy have gradually been developed.Hence,we reviewed the use of NRP1 in the context of tumorigenesis,progression,and treatment.

Neoantigens in precision cancer immunotherapy:from identification to clinical applications

Immunotherapies targeting cancer neoantigens are safe,effective,and precise.Neoantigens can be identified mainly by genomic techniques such as next-generation sequencing and high-throughput single-cell sequencing;proteomic techniques such as mass spectrometry;and bioinformatics tools based on high-throughput sequencing data,mass spectrometry data,and biological databases.Neoantigen-related therapies are widely used in clinical practice and include neoantigen vaccines,neoantigen-specific CD8+and CD4+T cells,and neoantigen-pulsed dendritic cells.In addition,neoantigens can be used as biomarkers to assess immunotherapy response,resistance,and prognosis.Therapies based on neoantigens are an important and promising branch of cancer immunotherapy.Unremitting efforts are needed to unravel the comprehensive role of neoantigens in anti-tumor immunity and to extend their clinical application.This review aimed to summarize the progress in neoantigen research and to discuss its opportunities and challenges in precision cancer immunotherapy.

New Concepts in Tumor Antigens:Their Significance in Future Immunotherapies for Tumors

The identification and molecular characterization of self-antigens expressed by human malignancies that are capable of elicitation of anti-tumor immune responses in patients have been an active field in tumor immunology. More than 2,000 tumor antigens have been identified, and most of these antigens are self-antigens. These significant progresses have led to the renaissance of tumor immunology and studies on anti-tumor immunotherapy. However, despite of the progress in the identification of self-tumor antigens, current antigen-specific immunotherapies for tumors are far less satisfied than expected, which reflects the urgent need to improve our understanding on self-tumor antigens. In order to develop more effective antigen specific anti-tumor immunotherapies and to monitor the responses to these immunotherapies in patients with tumors, many important fundamental questions need to be addressed. We propose for the first time that the studies in addressing the characteristics of self-tumor antigens and autoantigens are grouped as a new subject termed ＂antigenology＂. In this brief review, we would outline the progress in the identification of tumor antigens in solid tumors and hematologic malignancies, and overview the new concepts and principles of antigenology and their significance for future immunotherapies to these malignancies.

胆囊癌转化治疗及序贯手术治疗的几个关键问题

转化治疗可使初始不可切除肿瘤降期并达到R0切除,使病人获得手术机会,延长生存期。伴随系统治疗进步及综合治疗的不断创新,胆囊癌(GBC)转化治疗逐渐成为探索的热点。制定系统化转化战略时需高度重视GBC的异质性,不能简单遵循指南,应紧跟国际前沿,并对各治疗方案和评价指标的内涵保持清晰的认知,力求实现高度个体化的全程管理。在GBC转化治疗中,免疫治疗3.0模式未来可期,围手术期需高度重视免疫治疗相关不良反应的识别。目前转化人群筛选、转化策略制定、序贯手术时机把握、术后辅助治疗方案选择等诸多问题亟待深入探索,在基础和临床研究尚无法满足临床实战的大背景下,期待各方专家积极总结经验,加强协作,积极开展术前转化治疗和术后辅助治疗多中心临床研究,早日凝聚立足国情的GBC转化治疗共识。

It takes two: potential therapies and insights involving microglia and macrophages in glioblastoma

Microglia and macrophages, two myeloid cell lineages with different origins, make up the majority of immune cells present in glioblastoma (GBM). However, much of the literature does not distinguish between microglia and macrophages, despite a growing body of evidence that demonstrates key structural and functional differences between the cell types. Furthermore, the current M1/M2 paradigm used to sub-classify microglia and macrophages has proven to be incomplete at best, with the growing amount of in vivo and genomic data incompatible with this dichotomy. Finally, a number of studies have already established that in the setting of the GBM tumor microenvironment, both microglia and macrophages are complicit in tumor progression. This review highlights the differences between microglia and macrophages, particularly in the context of GBM, and discusses at length several potential therapeutic strategies made possible by understanding specific pro-tumor and anti-tumor pathways in these myeloid populations. Ultimately, investigating the differences between microglia and macrophages offers insight into the progression of GBM, its marked resistance to current immunotherapy regimens, and future directions for new treatment modalities.