New avenues for the treatment of immunotherapy-resistant pancreatic cancer

Pancreatic cancer(PC)is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide.However,due to its complexity,it ranks 7th in the list of the most lethal cancers worldwide.The pathogenesis of PC involves several complex processes,including familial genetic factors associated with risk factors such as obesity,diabetes mellitus,chronic pancreatitis,and smoking.Mutations in genes such as KRAS,TP53,and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and,consequently,cancer.In this context,some therapies are used for PC,one of which is immunotherapy,which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency.It is therefore clear that the tumor microenvironment(TME)has a huge impact on the resistance process,since cellular and non-cellular elements create an immunosuppressive environment,characterized by a dense desmoplastic stroma with cancerassociated fibroblasts,pancreatic stellate cells,extracellular matrix,and immunosuppressive cells.Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells,resulting in a shortage of CD8+T cells and limited expression of activation markers such as interferon-gamma.In this way,finding new strategies that make it possible to manipulate resistance mechanisms is necessary.Thus,techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance,the use of genetic manipulation in specific regions,such as microRNAs,the modulation of extrinsic and intrinsic factors associated with T cells,and,above all,therapeutic models that combine these modulation techniques constitute the promising future of PC therapy.Thus,this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process,resulting in a more efficient therapy for cancer patients and,consequently,a reduction in the lethality of this aggressive cancer.

Understanding the immune response and the current landscape of immunotherapy in pancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC)is an aggressive tumor with high lethality.Even with surgery,radiotherapy,chemotherapy,and other locoregional or systemic therapies,the survival rates for PDAC are low and have not significantly changed in the past decades.The special characteristics of the PDAC’s microenvironment and its complex immune escape mechanism need to be considered when designing novel therapeutic approaches in this disease.PDAC is characterized by chronic inflammation with a high rate of tumor-associated macrophages and myeloid-derived suppressor cells and a low rate of natural killer and effector T cells.The pancreatic microenvironment is a fibrotic,microvascularized stroma that isolates the tumor from systemic vascularization.Immunotherapy,a novel approach that has demonstrated effectiveness in certain solid tumors,has failed to show any practice-changing results in pancreatic cancer,with the exception of PDACs with mismatch repair deficiency and high tumor mutational burden,which show prolonged survival rates with immunotherapy.Currently,numerous clinical trials are attempting to assess the efficacy of immunotherapeutic strategies in PDAC,including immune checkpoint inhibitors,cancer vaccines,and adoptive cell transfer,alone or in combination with other immunotherapeutic agents,chemoradiotherapy,and other targeted therapies.A deep understanding of the immune response will help in the development of new therapeutic strategies leading to improved clinical outcomes for patients with PDAC.

Pancreatic ductal adenocarcinoma: Treatment hurdles, tumor microenvironment and immunotherapy

Pancreatic ductal adenocarcinoma(PDAC)is one of the most lethal diseases,with an average 5-year survival rate of less than 10%.Unfortunately,the majority of patients have unresectable,locally advanced,or metastatic disease at the time of diagnosis.Moreover,traditional treatments such as chemotherapy,surgery,and radiation have not been shown to significantly improve survival.Recently,there has been a swift increase in cancer treatments that incorporate immunotherapybased strategies to target all the stepwise events required for tumor initiation and progression.The results in melanoma,non-small-cell lung cancer and renal cell carcinoma are very encouraging.Unfortunately,the application of checkpoint inhibitors,including anti-CTLA4,anti-PD-1,and anti-PD-L1 antibodies,in pancreatic cancer has been disappointing.Many studies have revealed that the PDAC microenvironment supports tumor growth,promotes metastasis and consists of a physical barrier to drug delivery.Combination therapies hold great promise for enhancing immune responses to achieve a better therapeutic effect.In this review,we provide an outline of why pancreatic cancer is so lethal and of the treatment hurdles that exist.Particular emphasis is given to the role of the tumor microenvironment,and some of the latest and most promising studies on immunotherapy in PDAC are also presented.

Progress of tumor-associated macrophages in pancreatic cancer

Pancreatic cancer is a kind of highly aggressive malignant tumor of the digestive system.The treatment of local tumors is mainly surgical resection,but the indications are too harsh.For advanced pancreatic cancer,chemotherapy is the standard treatment,but patients have severe side effects and develop drug resistance.Tumor-associated macrophages in the tumor microenvironment of pancreatic cancer are the most abundant immune cells and play a very important role in tumor development and chemoresistance.Antitumor-associated macrophage therapy has shown some therapeutic potential.Therefore,this article reviews the mechanism of tumor-associated macrophages in pancreatic cancer and the progress of tumor-associated macrophage targeted therapy.

Pancreatic ductal adenocarcinoma immune microenvironment and immunotherapy prospects

The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) is non-immunogenic, which consists of the stellate cells, fibroblasts, immune cells, extracellular matrix, and some other immune suppressive molecules. This low tumor perfusion microenvironment with physical dense fibrotic stroma shields PDAC from traditional antitumor therapies like chemotherapy and various strategies that have been proven successful in other types of cancer. Immunotherapy has the potential to treat minimal and residual diseases and prevent recurrence with minimal toxicity, and studies in patients with metastatic and nonresectable disease have shown some efficacy. In this review, we highlighted the main components of the pancreatic tumor microenvironment, and meanwhile, summarized the advances of some promising immunotherapies for PDAC, including checkpoint inhibitors, chimeric antigen receptors T cells, and cancer vaccines. Based on our previous researches, we specifically discussed how granulocyte-macrophage colony stimulating factor based pancreatic cancer vaccine prime the pancreatic tumor microenvironment, and introduced some novel immunoadjuvants, like the stimulator of interferon genes.

Immune-related signature identifies IL1R2 as an immunological and prognostic biomarker in pancreatic cancer

Objective:Pancreatic cancer is one of the most aggressive malignancies,a robust prognostic signature and novel biomarkers are urgently needed for accurate stratification of the patients and optimization of clinical decision-making.Methods:A list of bioinformatic analysis were applied in public dataset to construct an immune-related signature.Furthermore,the most pivotal gene in the signature was identified.The potential mechanism of the core gene function was revealed through GSEA,CIBERSORT,ESTIMATE,immunophenoscore(IPS)algorithm,single-cell analysis,and functional experiment.Results:An immune-related prognostic signature and associated nomogram were constructed and validated.Among the genes constituting the signature,interleukin 1 receptor type II(IL1R2)was identified as the gene occupying the most paramount position in the risk signature.Meanwhile,knockdown of IL1R2 significantly inhibited the proliferation,invasion,and migration ability of pancreatic cancer cells.Additionally,high IL1R2 expression was associated with reduced CD8+T cell infiltration in pancreatic cancer microenvironment,which may be due to high programmed cell death-ligand-1(PD-L1)expression in cancer cells.Finally,the IPS algorithm proved that patients with high IL1R2 expression possessed a higher tumor mutation burden and a higher probability of benefiting from immunotherapy.Conclusion:In conclusion,our study constructed an efficient immune-related prognostic signature and identified the key role of IL1R2 in the development of pancreatic cancer,as well as its potential to serve as a biomarker for immunotherapy efficacy prediction for pancreatic cancer.

Making incurable pancreatic cancer curable

Pancreatic cancer is one of the deadliest malignancies,with limited effectiveness of standard therapies,resulting in little improvement in the 5-year survival rate over the past few decades.However,advanced radiotherapy techniques and emerging treatment modalities,such as immunotherapy and targeted therapy,are showing tremendous potential as effective treatment options for pancreatic cancer patients who were previously considered incurable.This review summarizes the current advances and challenges in pancreatic cancer treatment strategies and proposes further optimization directions,aiming to provide insights into the cure of incurable pancreatic cancer.

Immune checkpoints in targetedi-mmunotherapy of pancreatic cancer:New hope for clinical development

Immunotherapy has been recently considered as a promising alternative for cancer treatment.Indeed,targeting of immune checkpoint(ICP)strategies have shown significant success in human malignancies.However,despite remarkable success of cancer immunotherapy in pancreatic cancer(PCa),many of the developed immunotherapy methods show poor therapeutic outcomes in PCa with no or few effective treatment options thus far.In this process,immunosuppression in the tumor microenvironment(TME)is found to be the main obstacle to the effectiveness of antitumor immune response induced by an immunotherapy method.In this paper,the latest findings on the ICPs,which mediate immunosuppression in the TME have been reviewed.In addition,different approaches for targeting ICPs in the TME of PCa have been discussed.This review has also synopsized the cutting-edge advances in the latest studies to clinical applications of ICP-targeted therapy in PCa.

Tunable hybrid hydrogels with multicellular spheroids for modeling desmoplastic pancreatic cancer

The tumor microenvironment consists of diverse,complex etiological factors.The matrix component of pancreatic ductal adenocarcinoma(PDAC)plays an important role not only in physical properties such as tissue rigidity but also in cancer progression and therapeutic responsiveness.Although significant efforts have been made to model desmoplastic PDAC,existing models could not fully recapitulate the etiology to mimic and understand the progression of PDAC.Here,two major components in desmoplastic pancreatic matrices,hyaluronic acid-and gelatin-based hydrogels,are engineered to provide matrices for tumor spheroids composed of PDAC and cancer-associated fibroblasts(CAF).Shape analysis profiles reveals that incorporating CAF contributes to a more compact tissue formation.Higher expression levels of markers associated with proliferation,epithelial to mesenchymal transition,mechanotransduction,and progression are observed for cancer-CAF spheroids cultured in hyper desmoplastic matrix-mimicking hydrogels,while the trend can be observed when those are cultured in desmoplastic matrix-mimicking hydrogels with the presence of transforming growth factor-β1(TGF-β1).The proposed multicellular pancreatic tumor model,in combination with proper mechanical properties and TGF-β1 supplement,makes strides in developing advanced pancreatic models for resembling and monitoring the progression of pancreatic tumors,which could be potentially applicable for realizing personalized medicine and drug testing applications.

胰腺癌微环境治疗策略的进展与思考

胰腺癌恶性程度较高,明显的间质纤维化及肿瘤异质性是胰腺癌的重要特征,也是胰腺癌患者对目前传统化疗应答欠佳、预后极差的重要原因。因此,寻找有效的治疗策略是提高胰腺癌患者生存率的关键问题。鉴于胰腺癌"间质化"及"异质性"的特性,国内外学者致力于阐明肿瘤微环境在胰腺癌发展过程中的作用机制及寻找有效的微环境靶向治疗策略,以提高胰腺癌患者治疗反应率,实现对于胰腺癌患者精准治疗的目的。本文通过对胰腺癌的微环境研究现状及在精准治疗理念下的靶向胰腺癌微环境的最新进展进行概述,为进一步提高胰腺癌患者的生存率提供新思路。

胰腺癌免疫抑制性肿瘤微环境研究综述

胰腺癌是一种高度恶性的肿瘤,早期诊断困难且缺乏有效的治疗方法,导致预后极差。胰腺癌肿瘤微环境包含肿瘤细胞、免疫细胞、基质细胞、细胞外基质以及多种可溶性分子;其中,细胞外成分包括基质成分和可溶性因子等,在肿瘤的发生、发展、侵袭和转移过程中发挥重要作用。胰腺癌微环境中具有显著的免疫细胞浸润,以免疫抑制为突出特征。肿瘤细胞一方面编辑免疫系统,使其无法被免疫系统识别;另一方面招募和激活各种免疫抑制性细胞如胰腺星状细胞、髓系来源抑制细胞、肿瘤相关巨噬细胞和调节性T细胞等,进而分泌免疫抑制性分子,影响抗肿瘤免疫细胞的功能,抑制宿主的抗肿瘤免疫反应,造成肿瘤的免疫逃逸,促进肿瘤的发展转移。该文讨论胰腺癌肿瘤微环境各种免疫抑制成分的作用机制,并总结胰腺癌免疫治疗的最新成果,以期为胰腺癌免疫抑制性肿瘤微环境的研究以及胰腺癌的免疫治疗提供新的思路。

肿瘤浸润淋巴细胞在胰腺癌中研究进展

胰腺癌五年生存率低于5%,现有的治疗手段治疗效果有限,针对胰腺癌的治疗仍面临巨大挑战.肿瘤浸润淋巴细胞(tumor infiltrating lymphocyte,TIL)是肿瘤微环境的重要组成部分,起到主导肿瘤微环境局部免疫反应的作用,是许多癌症的有利预后因素.TIL能够特异性地识别肿瘤细胞,通过细胞免疫对这些肿瘤细胞进行杀伤.TIL疗法已经被证明在黑色素瘤、宫颈癌、乳腺癌等实体瘤中具有良好的治疗效果,但是应用TIL治疗胰腺癌仍然存在一些难点,包括新生抗原的筛选、TIL快速扩增、导向到肿瘤部位及细胞衰竭.本文将就近年来人们对TIL在胰腺癌中的研究进行概述,挖掘TIL在胰腺癌治疗中的潜在应用价值.

肿瘤相关巨噬细胞在胰腺癌中的研究进展

胰腺癌是消化系统极具侵袭性的恶性肿瘤。其中局部肿瘤的治疗方式主要是手术切除,但适应证过于苛刻。对于晚期胰腺癌,化疗是标准疗法,但患者副作用严重且会产生耐药性。胰腺癌肿瘤微环境中的肿瘤相关巨噬细胞是含量最高的免疫细胞,在肿瘤发展和化学耐药中起着非常重要的作用。抗肿瘤相关巨噬细胞治疗显示出一定的治疗潜力。因此本文对肿瘤相关巨噬细胞在胰腺癌中的作用机制及肿瘤相关巨噬细胞靶向治疗的研究进展作一综述。

胰腺癌抗纤维化治疗研究进展

胰腺癌的恶性程度高、侵袭性强、生存率低,其肿瘤微环境中高度的间质纤维化在胰腺癌发生和发展过程中具有重要作用,并严重影响胰腺肿瘤的治疗效果。近年来,逆转胰腺癌纤维化肿瘤微环境已经成为胰腺癌治疗的新思路。基于此,本文分别从靶向间质细胞(胰腺星状细胞和相关成纤维细胞)、靶向间质成分(胶原和透明质酸)和靶向纤维化机制(上皮-间充质转化、hedgehog信号途径和伤口愈合)三个方面综述了胰腺癌在抑制纤维化治疗方面的最新研究进展,并对当前纤维化研究中细胞与动物纤维化模型的构建进行了介绍,以期为胰腺癌的肿瘤微环境治疗提供参考。

基于免疫检查点抑制剂靶向胰腺癌微环境的联合免疫治疗策略

胰腺癌是一种较为难治且恶性程度极高的肿瘤,其发病隐匿,进展迅速。传统的治疗方法对胰腺癌患者效果不佳,以免疫检查点抑制剂为代表的免疫治疗在非小细胞肺癌和黑色素瘤等多种恶性肿瘤中显示出良好的效果,但对胰腺癌患者治疗效果有限,这可能与胰腺癌独特的肿瘤微环境有关。针对胰腺癌微环境中的特定位点进行靶向调节,促使肿瘤微环境由免疫抑制状态向免疫激活状态转变,可能是增强免疫检查点抑制剂治疗效果的有效策略,因此,联合免疫检查点抑制剂与靶向治疗可能在胰腺癌治疗中具有良好的应用前景。本文将对靶向胰腺癌肿瘤微环境的药物作用机制及其与免疫检查点抑制剂联合应用的策略进行综述,以期为胰腺癌的联合免疫治疗提供有效参考。

一例化疗联合免疫治疗无效胰腺癌患者再联合靶向治疗有效

一例68岁男性患者因纳差乏力就诊,影像学和肝病灶穿刺活检结果提示胰腺体尾癌伴肝脏多发转移,肿瘤标志物糖类抗原(CA)199为2003.4 U/mL。患者采用改良FOLFIRINOX化疗方案联合免疫检查点抑制剂(派安普利单抗)治疗两周期后胰尾及肝脏肿块未减小,CA199水平较前明显升高。从第三周期加用靶向药物安罗替尼后发现胰腺病灶及肝转移灶较前明显缩小,行腹腔镜下胰体尾切除、脾切除及肝转移灶切除术。患者术后再次行三周期改良FOLFIRINOX联合安罗替尼及派安普利单抗治疗,三周期后采用安罗替尼及派安普利单抗维持治疗,随访患者至今(确诊后近19个月)未见明显复发。

肿瘤相关中性粒细胞与胰腺癌关系的研究进展

胰腺癌是一种起病隐匿、预后不良的消化系统恶性肿瘤,具有早期诊断困难、进展期生存时间短等特点。胰腺癌的肿瘤微环境(Tumor microenvironment,TME)中常常伴有大量免疫细胞的浸润,而肿瘤相关中性粒细胞(Tumor-associated neutrophils,TANs)作为TME的重要组成部分,在肿瘤的进程中起着重要作用。相关研究表明,TANs在胰腺癌的TME中发挥多种作用。本文从TANs与胰腺癌的关系进行综述,为理解胰腺癌发生机制与提出新疗法提供思路。

胰腺癌免疫治疗的研究进展

胰腺癌是一种较为常见的消化系统肿瘤,恶性程度极高。由于胰腺癌发病隐匿,缺乏有效的早期诊断方法,确诊时大部分患者已为中晚期,错过了最佳手术时机。而针对中晚期胰腺癌,目前尚缺乏有效的治疗方案。要改善胰腺癌的治疗现状,不能仅靠手术治疗,化疗、免疫治疗及靶向治疗同样重要。近年来,免疫治疗在多种恶性肿瘤的治疗中取得重大进展,在胰腺癌的治疗中也有所突破。本文对近年来胰腺癌免疫治疗的研究进展做一概述,展示胰腺癌免疫治疗领域的研究进展。

调节性T细胞在胰腺癌免疫治疗中的作用机制与应用策略

免疫治疗在胰腺癌的临床试验中疗效欠佳,主要原因在于胰腺癌具有高度免疫抑制的肿瘤微环境(tumor microenvironment,TME)。调节性T细胞(regulatory T cells,Tregs)是一类控制自身免疫反应的T细胞亚群,也是免疫抑制性TME的主要组成成分之一。Tregs能调控机体免疫反应强度,抑制效应T细胞的功能和活性进而诱导免疫耐受,维持免疫应答稳态。在胰腺癌TME中,Tregs通过抑制机体免疫反应从而介导肿瘤细胞发生免疫逃逸,影响患者的疗效与预后。本综述总结Tregs在胰腺癌免疫微环境中的作用机制及在胰腺癌中的临床意义,以期为胰腺癌免疫治疗提供更多的新思路。

人源性异种移植模型在胰腺癌个体化治疗研究中的应用

本文介绍了胰腺癌人源性异种移植(patient-derived xenograft,PDX)模型的基本特征、建模方法及模型应用中存在的问题,阐述了PDX模型在胰腺癌个体化药物筛选和耐药机制研究中的可行性。常规的胰腺癌标准化疗方案及联合用药疗效低下,因此,需要关注靶向重塑胰腺癌微环境抗肿瘤研究的重要性以期为研究者们提供新的思路,合理地使用该模型开展胰腺癌的研究,为胰腺癌患者提供更加高效的个体化治疗方案。