Oncoimmunology最新文献

{"title":"CD4+ T cell-derived IL-22 enhances liver metastasis by promoting angiogenesis.","authors":"Tao Zhang, Ramez Wahib, Dimitra E Zazara, Jöran Lücke, Ahmad Mustafa Shiri, Jan Kempski, Lilan Zhao, Theodora Agalioti, Andres Pablo Machicote, Olympia Giannou, Ioannis Belios, Rongrong Jia, Siwen Zhang, Joseph Tintelnot, Hannes Seese, Julia Kristin Grass, Baris Mercanoglu, Louisa Stern, Pasquale Scognamiglio, Mohammad Fard-Aghaie, Philipp Seeger, Jonas Wakker, Marius Kemper, Benjamin Brunswig, Anna Duprée, Panagis M Lykoudis, Anastasia Pikouli, Emmanouil Giorgakis, Pablo Stringa, Natalia Lausada, Maria Virginia Gentilini, Gabriel E Gondolesi, Kai Bachmann, Philipp Busch, Rainer Grotelüschen, Ioannis C Maroulis, Petra C Arck, Ryosuke Nakano, Angus W Thomson, Tarik Ghadban, Michael Tachezy, Nathaniel Melling, Eike-Gert Achilles, Victor G Puelles, Felix Nickel, Thilo Hackert, Oliver Mann, Jakob R Izbicki, Jun Li, Nicola Gagliani, Samuel Huber, Anastasios D Giannou","doi":"10.1080/2162402X.2023.2269634","DOIUrl":"10.1080/2162402X.2023.2269634","url":null,"abstract":"<p><p>Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2269634"},"PeriodicalIF":7.2,"publicationDate":"2023-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2e/86/KONI_12_2269634.PMC10591777.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50159070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>PD-L1</i> (<i>CD274</i>) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma.","authors":"Niklas Klümper, Lennert Wüst, Jonas Saal, Damian J Ralser, Romina Zarbl, Jonas Jarczyk, Johannes Breyer, Danijel Sikic, Bernd Wullich, Christian Bolenz, Florian Roghmann, Michael Hölzel, Manuel Ritter, Sebastian Strieth, Arndt Hartmann, Philipp Erben, Ralph M Wirtz, Jennifer Landsberg, Dimo Dietrich, Markus Eckstein","doi":"10.1080/2162402X.2023.2267744","DOIUrl":"10.1080/2162402X.2023.2267744","url":null,"abstract":"<p><p>PD-L1 status assessed by immunohistochemistry (IHC) has failed to reliably predict outcomes for patients with metastatic urothelial carcinoma (mUC) on immune checkpoint blockade (ICB). <i>PD-L1</i> promoter methylation is an epigenetic mechanism that has been shown to regulate <i>PD-L1</i> mRNA expression in various malignancies. The aim of our present study was to evaluate the predictive potential of <i>PD-L1</i> promoter methylation status (<i>mPD-L1</i>) in ICB-treated mUC compared to conventional IHC-based PD-L1 assessment. We quantified <i>mPD-L1</i> in formalin-fixed and paraffin-embedded tissue sections using an established quantitative methylation-specific PCR assay (qMSP) in a well-characterized multicenter ICB-treated cohort comprising <i>N</i> = 107 patients with mUC. Additionally, PD-L1 protein expression in tumor tissues was assessed using regulatory approved IHC protocols. The effect of pharmacological hypomethylation by the DNA methyltransferase inhibitor decitabine in combination with interferon-γ stimulation in urothelial carcinoma cell lines was investigated by IHC and FACS. <i>mPD-L1</i> hypomethylation predicted objective response rate at the first staging on ICB. Patients with tumors categorized as <i>PD-L1</i> hypomethylated (lower quartile) showed significantly prolonged progression-free (PFS) and overall survival (OS) after ICB initiation. In contrast, PD-L1 protein expression status neither correlated with response nor survival. In multivariable Cox regression analyses, <i>PD-L1</i> promoter hypermethylation remained an independent predictor of unfavorable PFS and OS. In urothelial carcinoma cell lines, pharmacological demethylation led to an upregulation of membranous PD-L1 expression and an enhanced inducibility of PD-L1 expression by interferon γ. Hypomethylation of the <i>PD-L1</i> promoter is a promising predictive biomarker for response to ICB in patients with mUC.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2267744"},"PeriodicalIF":7.2,"publicationDate":"2023-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/60/52/KONI_12_2267744.PMC10588513.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49693160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A mitochondrial checkpoint to adaptive anticancer immunity.","authors":"Oliver Kepp, Peng Liu, Guido Kroemer, Lorenzo Galluzzi","doi":"10.1080/2162402X.2023.2271693","DOIUrl":"10.1080/2162402X.2023.2271693","url":null,"abstract":"<p><p>BCL2 robustly preserves mitochondrial integrity, hence inhibiting innate immune signaling and apoptotic cell death in several cell types. Here, we comment on our recent data demonstrating that BCL2 also limits the ability of dendritic cells to elicit adaptive immune responses, lending support to a universal immunosuppressive function for the mitochondrial immune checkpoint.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2271693"},"PeriodicalIF":7.2,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6e/d6/KONI_12_2271693.PMC10583618.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49683862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody.","authors":"Hayat Bähr-Mahmud,&nbsp;Ursula Ellinghaus,&nbsp;Christiane R Stadler,&nbsp;Leyla Fischer,&nbsp;Claudia Lindemann,&nbsp;Anuhar Chaturvedi,&nbsp;Jan Diekmann,&nbsp;Stefan Wöll,&nbsp;Imke Biermann,&nbsp;Bernhard Hebich,&nbsp;Caroline Scharf,&nbsp;Manuela Siefke,&nbsp;Alexandra S Roth,&nbsp;Martin Rao,&nbsp;Kerstin Brettschneider,&nbsp;Eva-Maria Ewen,&nbsp;Uğur Şahin,&nbsp;Özlem Türeci","doi":"10.1080/2162402X.2023.2255041","DOIUrl":"10.1080/2162402X.2023.2255041","url":null,"abstract":"<p><p>IMAB362/Zolbetuximab, a first-in-class IgG1 antibody directed against the cancer-associated gastric-lineage marker CLDN18.2, has recently been reported to have met its primary endpoint in two phase 3 trials as a first-line treatment in combination with standard of care chemotherapy in CLDN18.2-positive Her2 negative advanced gastric cancer. Here we characterize the preclinical pharmacology of BNT141, a nucleoside-modified RNA therapeutic encoding the sequence of IMAB362/Zolbetuximab, formulated in lipid nanoparticles (LNP) for liver uptake. We show that the mRNA-encoded antibody displays a stable pharmacokinetic profile in preclinical animal models, mediates CLDN18.2-restricted cytotoxicity comparable to IMAB362 recombinant protein and inhibits human tumor xenograft growth in immunocompromised mice. BNT141 administration did not perpetrate mortality, clinical signs of toxicity, or gastric pathology in animal studies. A phase 1/2 clinical trial with BNT141 mRNA-LNP has been initiated in advanced CLDN18.2-expressing solid cancers (NCT04683939).</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2255041"},"PeriodicalIF":7.2,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/aa/69/KONI_12_2255041.PMC10583639.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49683863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dipeptidyl peptidase 4 inhibition sensitizes radiotherapy by promoting T cell infiltration.","authors":"Yu Tian,&nbsp;Lingyi Kong,&nbsp;Yan Li,&nbsp;Zhiyun Liao,&nbsp;Xing Cai,&nbsp;Suke Deng,&nbsp;Xiao Yang,&nbsp;Bin Zhang,&nbsp;Yijun Wang,&nbsp;Zhanjie Zhang,&nbsp;Bian Wu,&nbsp;Lu Wen,&nbsp;Fang Huang,&nbsp;Yan Hu,&nbsp;Chao Wan,&nbsp;Yifei Liao,&nbsp;Yajie Sun,&nbsp;Kunyu Yang","doi":"10.1080/2162402X.2023.2268257","DOIUrl":"10.1080/2162402X.2023.2268257","url":null,"abstract":"<p><p>Radiotherapy could regulate systemic antitumor immunity, while the immune state in the tumor microenvironment (TME) also affects the efficacy of radiotherapy. We have found that higher CD8⁺ T cell infiltration is associated with longer overall survival of lung adenocarcinoma and melanoma patients receiving radiotherapy. 8-Gray radiation increased the transcriptional levels of chemokines in tumor cells <i>in vitro</i>. However, it was not sufficient to induce significant lymphocyte infiltration <i>in vivo</i>. Dipeptidyl peptidase 4 (DPP4) has been reported to inactivate chemokines via post-translational truncation. Single-cell sequencing revealed that dendritic cells (DCs) had a higher DPP4 expression among other cells in the TME and upregulated DPP4 expression after radiation. Combining a DPP4 inhibitor with radiotherapy could promote chemokines expression and T cell infiltration in the TME, enhancing the antitumor effect of radiotherapy. Moreover, this therapy further enhanced the therapeutic efficacy of anti-PD-1. In this study, we demonstrated the underlying mechanism of why radiotherapy failed to induce sufficient T cell infiltration and proposed an effective strategy to promote T cell infiltration and sensitize radiotherapy. These findings demonstrate the translational value of DPP4 inhibition as a complementary approach to enhance the efficacy of radiotherapy and the combination of radiotherapy with immunotherapy.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2268257"},"PeriodicalIF":7.2,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d1/96/KONI_12_2268257.PMC10578189.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41240034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"scRNA-seq reveals ATPIF1 activity in control of T cell antitumor activity.","authors":"Genshen Zhong,&nbsp;Qi Wang,&nbsp;Ying Wang,&nbsp;Ying Guo,&nbsp;Meiqi Xu,&nbsp;Yaya Guan,&nbsp;Xiaoying Zhang,&nbsp;Minna Wu,&nbsp;Zhishan Xu,&nbsp;Weidong Zhao,&nbsp;Hongkai Lian,&nbsp;Hui Wang,&nbsp;Jianping Ye","doi":"10.1080/2162402X.2022.2114740","DOIUrl":"https://doi.org/10.1080/2162402X.2022.2114740","url":null,"abstract":"<p><p>ATP synthase inhibitory factor 1 (ATPIF1) is a mitochondrial protein with an activity in inhibition of F₁F_o-ATP synthase. ATPIF1 activity remains unknown in the control of immune activity of T cells. In this study, we identified ATPIF1 activity in the induction of CD8⁺ T cell function in tumor models through genetic approaches. ATPIF1 gene inactivation impaired the immune activities of CD8⁺ T cells leading to quick tumor growth (B16 melanoma and Lewis lung cancer) in ATPIF1-KO mice. The KO T cells exhibited a reduced activity in proliferation and IFN-γ secretion with metabolic reprogramming of increased glycolysis and decreased oxidative phosphorylation (OXPHOS) after activation. T cell exhaustion was increased in the tumor infiltrating leukocytes (TILs) of KO mice as revealed by the single-cell RNA sequencing (scRNA-seq) and confirmed by flow cytometry. In contrast, ATPIF1 overexpression in T cells increased expression of IFN-γ and Granzyme B, subset of central memory T cells in CAR-T cells, and survival rate of NALM-6 tumor-bearing mice. These data demonstrate that ATPIF1 deficiency led to tumor immune deficiency through induction of T cell exhaustion. ATPIF1 overexpression enhanced the T cell tumor immunity. Therefore, ATPIF1 is a potential molecular target in the modulation of antitumor immunity of CD8⁺ T cells in cancer immunotherapy. Induction of ATPIF1 activity may promote CAR-T activity in cancer therapy.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"11 1","pages":"2114740"},"PeriodicalIF":7.2,"publicationDate":"2022-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/01/f3/KONI_11_2114740.PMC9397437.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33437927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A T-cell engaging bispecific antibody with a tumor-selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancer.","authors":"Brian C Avanzino, Kirthana Prabhakar, Pranjali Dalvi, Sharon Hartstein, Hannes Kehm, Aarti Balasubramani, Andrew A Boudreau, Ben Buelow, Karen Chang, Laura M Davison, Suhasini Iyer, Vidyut Kalwit, Kristin Lewis Wilson, Harbani K Malik-Chaudhry, Will Pierson, Geovanni Pineda, Udaya S Rangaswamy, Sowmya Saiganesh, Ute Schellenberger, Harshad S Ugamraj, Rodolfovan D Yabut, Roland Buelow, Jocelyn Chapman, Nathan D Trinklein, Katherine E Harris","doi":"10.1080/2162402X.2022.2113697","DOIUrl":"10.1080/2162402X.2022.2113697","url":null,"abstract":"<p><p>The use of T-cell engagers (TCEs) to treat solid tumors is challenging, and several have been limited by narrow therapeutic windows due to substantial on-target, off-tumor toxicities due to the expression of low levels of target antigens on healthy tissues. Here, we describe TNB-928B, a fully human TCE that has a bivalent binding arm for folate receptor alpha (FRα) to selectively target FRα overexpressing tumor cells while avoiding the lysis of cells with low levels of FRα expression. The bivalent design of the FRα binding arm confers tumor selectivity due to low-affinity but high-avidity binding to high FRα antigen density cells. TNB-928B induces preferential effector T-cell activation, proliferation, and selective cytotoxic activity on high FRα expressing cells while sparing low FRα expressing cells. In addition, TNB-928B induces minimal cytokine release compared to a positive control TCE containing OKT3. Moreover, TNB-928B exhibits substantial <i>ex vivo</i> tumor cell lysis using endogenous T-cells and robust tumor clearance <i>in vivo</i>, promoting T-cell infiltration and antitumor activity in mouse models of ovarian cancer. TNB-928B exhibits pharmacokinetics similar to conventional antibodies, which are projected to enable favorable administration in humans. TNB-928B is a novel TCE with enhanced safety and specificity for the treatment of ovarian cancer.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"11 1","pages":"2113697"},"PeriodicalIF":7.2,"publicationDate":"2022-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ad/33/KONI_11_2113697.PMC9397469.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33437926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}