Pub Date : 2024-05-02DOI: 10.1158/2326-6066.CIR-23-0652
Muhammad A Saeed, Bo Peng, Kevin Kim, Kavita Rawat, Lindsey M Kuehm, Zoe R Siegel, Ariel Borkowski, Nabih Habib, Brian Van Tine, Nadeem Sheikh, Vu Tuyen, Daniel L J Thorek, Todd A Fehniger, Russell K Pachynski
Sipuleucel-T (sip-T) is the only FDA-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). To elucidate parameters of the response profile to this therapy, we report high-dimensional analyses of sip-T using cytometry by time of flight (CyTOF) and show a lymphoid predominance, with CD3+ T cells constituting the highest proportion (median ∼60%) of sip-T, followed by B cells, and natural killer (NK) and NKT cells. We hypothesized that treatment of sip-T with homeostatic cytokines known to activate/expand effector lymphocytes could augment efficacy against prostate tumors. Of the cytokines tested, IL15 was the most effective at enhancing activation and proliferation of effector lymphocytes, as well as augmenting tumor cytotoxicity in vitro. Co-culture of sip-T with IL15 and control or prostate-relevant antigens showed substantial activation and expansion of CD8+ T cells and NKT cells in an antigen-specific manner. Adoptive transfer of IL15-treated sip-T into NSG mice resulted in more potent prostate tumor growth inhibition compared with control sip-T. Evaluation of tumor-infiltrating lymphocytes revealed a 2- to 14-fold higher influx of sip-T and a significant increase in IFNγ producing CD8+ T cells and NKT cells within the tumor microenvironment in the IL15 group. In conclusion, we put forward evidence that IL15 treatment can enhance the functional antitumor immunity of sip-T, providing rationale for combining IL15 or IL15 agonists with sip-T to treat patients with mCRPC.
Sipuleucel-T(sip-T)是美国食品及药物管理局(FDA)批准的唯一一种治疗转移性抗性前列腺癌(mCRPC)的自体细胞免疫疗法。为了阐明这种疗法的反应谱参数,我们利用飞行时间细胞计数法(CyTOF)对 sip-T 进行了高维分析,结果显示 sip-T 以淋巴细胞为主,CD3+ T 细胞在 sip-T 中占的比例最高(中位数约为 60%),其次是 B 细胞、自然杀伤细胞(NK)和 NKT 细胞。我们假设,用已知能激活/扩增效应淋巴细胞的平衡细胞因子处理 sip-T,能增强对前列腺肿瘤的疗效。在测试的细胞因子中,IL-15 在增强效应淋巴细胞的活化和增殖以及增强体外肿瘤细胞毒性方面最为有效。用 IL-15 和对照抗原或前列腺相关抗原共同培养 sip-T,结果显示 CD8+ T 细胞和 NKT 细胞以抗原特异性的方式被大量激活和扩增。与对照sip-T相比,将IL-15处理过的sip-T采纳性转移到NSG小鼠体内能更有效地抑制前列腺肿瘤的生长。对肿瘤浸润淋巴细胞的评估显示,IL-15组的sip-T流入量比对照组高2-14倍,肿瘤微环境(TME)中产生IFN-γ的CD8+ T细胞和NKT细胞显著增加。总之,我们提出了IL-15治疗可增强sip-T功能性抗肿瘤免疫的证据,为将IL-15或IL-15激动剂与sip-T联合治疗mCRPC患者提供了理论依据。
{"title":"High-Dimensional Analyses Reveal IL15 Enhances Activation of Sipuleucel-T Lymphocyte Subsets and Reverses Immunoresistance.","authors":"Muhammad A Saeed, Bo Peng, Kevin Kim, Kavita Rawat, Lindsey M Kuehm, Zoe R Siegel, Ariel Borkowski, Nabih Habib, Brian Van Tine, Nadeem Sheikh, Vu Tuyen, Daniel L J Thorek, Todd A Fehniger, Russell K Pachynski","doi":"10.1158/2326-6066.CIR-23-0652","DOIUrl":"10.1158/2326-6066.CIR-23-0652","url":null,"abstract":"<p><p>Sipuleucel-T (sip-T) is the only FDA-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). To elucidate parameters of the response profile to this therapy, we report high-dimensional analyses of sip-T using cytometry by time of flight (CyTOF) and show a lymphoid predominance, with CD3+ T cells constituting the highest proportion (median ∼60%) of sip-T, followed by B cells, and natural killer (NK) and NKT cells. We hypothesized that treatment of sip-T with homeostatic cytokines known to activate/expand effector lymphocytes could augment efficacy against prostate tumors. Of the cytokines tested, IL15 was the most effective at enhancing activation and proliferation of effector lymphocytes, as well as augmenting tumor cytotoxicity in vitro. Co-culture of sip-T with IL15 and control or prostate-relevant antigens showed substantial activation and expansion of CD8+ T cells and NKT cells in an antigen-specific manner. Adoptive transfer of IL15-treated sip-T into NSG mice resulted in more potent prostate tumor growth inhibition compared with control sip-T. Evaluation of tumor-infiltrating lymphocytes revealed a 2- to 14-fold higher influx of sip-T and a significant increase in IFNγ producing CD8+ T cells and NKT cells within the tumor microenvironment in the IL15 group. In conclusion, we put forward evidence that IL15 treatment can enhance the functional antitumor immunity of sip-T, providing rationale for combining IL15 or IL15 agonists with sip-T to treat patients with mCRPC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139971035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-02DOI: 10.1158/2326-6066.CIR-23-0467
Yimei Jin, Takahiko Miyama, Alexandria Brown, Tomo Hayase, Xingzhi Song, Anand K Singh, Licai Huang, Ivonne I Flores, Lauren K McDaniel, Israel Glover, Taylor M Halsey, Rishika Prasad, Valerie Chapa, Saira Ahmed, Jianhua Zhang, Kunal Rai, Christine B Peterson, Gregory Lizee, Jennifer Karmouch, Eiko Hayase, Jeffrey J Molldrem, Chia-Chi Chang, Wen-Bin Tsai, Robert R Jenq
Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell-APC aggregates were detected by dual-reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 antigen derived from human papillomavirus type 16 (HPV16), Tsyn-seq successfully enriched the correct cognate antigen from a cDNA library derived from an HPV16-positive cervical cancer cell line. Tsyn-seq provides a method for rapidly identifying antigens recognized by TCRs of interest from a tumor cDNA library. See related Spotlight by Makani and Joglekar, p. 515.
在全基因组范围内快速鉴定 T 细胞受体(TCR)的多肽-主要组织相容性复合体靶标的工具尚未普及。我们提出了一种新的抗原筛选方法--T-synapse(Tsyn)报告系统,它包括带有 Fas 诱导 NF-κB 报告的抗原递呈细胞(APC)和带有活化 T 细胞核因子(NFAT)报告的 T 细胞。为了从 cDNA 文库中功能性地筛选目标抗原,利用双重报告活性检测了T细胞-APC 聚合体的高效相互作用,并通过流式分拣进行了富集,然后通过深度测序(Tsyn-seq)量化了抗原鉴定。当把 Tsyn-seq 应用于先前表征的特异于人类乳头瘤病毒 16 型(HPV16)E7 抗原的 TCR 时,它成功地从来自 HPV16 阳性宫颈癌细胞系的 cDNA 文库中富集出了正确的同源抗原。Tsyn-seq 提供了一种从肿瘤 cDNA 文库中快速鉴定 TCR 识别的抗原的方法。
{"title":"Tsyn-Seq: a T-cell Synapse-Based Antigen Identification Platform.","authors":"Yimei Jin, Takahiko Miyama, Alexandria Brown, Tomo Hayase, Xingzhi Song, Anand K Singh, Licai Huang, Ivonne I Flores, Lauren K McDaniel, Israel Glover, Taylor M Halsey, Rishika Prasad, Valerie Chapa, Saira Ahmed, Jianhua Zhang, Kunal Rai, Christine B Peterson, Gregory Lizee, Jennifer Karmouch, Eiko Hayase, Jeffrey J Molldrem, Chia-Chi Chang, Wen-Bin Tsai, Robert R Jenq","doi":"10.1158/2326-6066.CIR-23-0467","DOIUrl":"10.1158/2326-6066.CIR-23-0467","url":null,"abstract":"<p><p>Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell-APC aggregates were detected by dual-reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 antigen derived from human papillomavirus type 16 (HPV16), Tsyn-seq successfully enriched the correct cognate antigen from a cDNA library derived from an HPV16-positive cervical cancer cell line. Tsyn-seq provides a method for rapidly identifying antigens recognized by TCRs of interest from a tumor cDNA library. See related Spotlight by Makani and Joglekar, p. 515.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11065584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139740415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-02DOI: 10.1158/2326-6066.cir-23-0826
Michelle Brennan, David DeBruin, Chinye Nwokolo, Katey S. Hunt, Alexander Piening, Maureen J. Donlin, Stephen T. Ferris, Ryan M. Teague, Richard J. DiPaolo, Elise Alspach
Emerging evidence in preclinical models demonstrates that antitumor immunity is not equivalent between males and females. However, more investigation in patients and across a wider range of cancer types is needed to fully understand sex as a variable in tumor immune responses. We investigated differences in T-cell responses between male and female patients with lung cancer by performing sex-based analysis of single cell transcriptomic datasets. We found that the transcript encoding CXC motif chemokine ligand 13 (CXCL13), which has recently been shown to correlate with T-cell tumor specificity, is expressed at greater levels in T cells isolated from female compared to male patients. Furthermore, increased expression of CXCL13 was associated with response to PD-1–targeting immunotherapy in female but not male patients. These findings suggest that there are sex-based differences in T-cell function required for response to anti–PD-1 therapy in lung cancer that may need to be considered during patient treatment decisions.
临床前模型的新证据表明,男性和女性的抗肿瘤免疫力并不相同。然而,要充分了解性别作为肿瘤免疫反应中的一个变量,还需要对患者和更广泛的癌症类型进行更多的调查。我们通过对单细胞转录组数据集进行基于性别的分析,研究了肺癌男女患者之间 T 细胞反应的差异。我们发现,与男性患者相比,编码 CXC motif 趋化因子配体 13(CXCL13)的转录本在女性患者分离出的 T 细胞中的表达水平更高。此外,CXCL13表达的增加与女性患者而非男性患者对PD-1靶向免疫疗法的反应有关。这些研究结果表明,肺癌患者对抗PD-1疗法产生反应所需的T细胞功能存在性别差异,患者在做出治疗决定时可能需要考虑到这一点。
{"title":"T-cell expression of CXCL13 is associated with immunotherapy response in a sex-dependent manner in patients with lung cancer","authors":"Michelle Brennan, David DeBruin, Chinye Nwokolo, Katey S. Hunt, Alexander Piening, Maureen J. Donlin, Stephen T. Ferris, Ryan M. Teague, Richard J. DiPaolo, Elise Alspach","doi":"10.1158/2326-6066.cir-23-0826","DOIUrl":"https://doi.org/10.1158/2326-6066.cir-23-0826","url":null,"abstract":"Emerging evidence in preclinical models demonstrates that antitumor immunity is not equivalent between males and females. However, more investigation in patients and across a wider range of cancer types is needed to fully understand sex as a variable in tumor immune responses. We investigated differences in T-cell responses between male and female patients with lung cancer by performing sex-based analysis of single cell transcriptomic datasets. We found that the transcript encoding CXC motif chemokine ligand 13 (CXCL13), which has recently been shown to correlate with T-cell tumor specificity, is expressed at greater levels in T cells isolated from female compared to male patients. Furthermore, increased expression of CXCL13 was associated with response to PD-1–targeting immunotherapy in female but not male patients. These findings suggest that there are sex-based differences in T-cell function required for response to anti–PD-1 therapy in lung cancer that may need to be considered during patient treatment decisions.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140832690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-02DOI: 10.1158/2326-6066.CIR-24-0239
Venkata Krishna Kanth Makani, Alok V Joglekar
The pivotal role of T cell responses has been well studied in both protective and destructive scenarios. T cells recognize peptide epitopes presented on Human Leukocyte Antigens (HLA) through their surface T cell receptors (TCR). Advances in single-cell RNA sequencing have identified millions of TCRs, but only a minuscule fraction of them have known epitopes. Recently, cell-based T cell antigen discovery platforms have emerged onto the landscape. Here, Jin and colleagues, report a novel antigen discovery platform called Tsyn-seq that relies on sequencing TCR-peptide-HLA-induced synapses for genome-wide epitope screening. See related article by Jin et al., p. 530 (3).
人们对 T 细胞反应在保护性和破坏性情况下的关键作用进行了深入研究。T 细胞通过其表面的 T 细胞受体 (TCR) 识别人类白细胞抗原 (HLA) 上的肽表位。单细胞 RNA 测序技术的进步已经发现了数百万个 TCR,但其中只有极少部分具有已知表位。最近,基于细胞的 T 细胞抗原发现平台崭露头角。在这里,Jin 及其同事报告了一种名为 Tsyn-seq 的新型抗原发现平台,该平台依靠对 TCR 肽-HLA 诱导的突触进行测序来进行全基因组表位筛选。请参见 Jin 等人的相关文章,第 xxxx 页。
{"title":"Living in Syn: T Cell Antigen Identification Based on Synapse Sequencing.","authors":"Venkata Krishna Kanth Makani, Alok V Joglekar","doi":"10.1158/2326-6066.CIR-24-0239","DOIUrl":"10.1158/2326-6066.CIR-24-0239","url":null,"abstract":"<p><p>The pivotal role of T cell responses has been well studied in both protective and destructive scenarios. T cells recognize peptide epitopes presented on Human Leukocyte Antigens (HLA) through their surface T cell receptors (TCR). Advances in single-cell RNA sequencing have identified millions of TCRs, but only a minuscule fraction of them have known epitopes. Recently, cell-based T cell antigen discovery platforms have emerged onto the landscape. Here, Jin and colleagues, report a novel antigen discovery platform called Tsyn-seq that relies on sequencing TCR-peptide-HLA-induced synapses for genome-wide epitope screening. See related article by Jin et al., p. 530 (3).</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140334755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-02DOI: 10.1158/2326-6066.CIR-23-0873
Katie E Blise, Shamilene Sivagnanam, Courtney B Betts, Konjit Betre, Nell Kirchberger, Benjamin J Tate, Emma E Furth, Andressa Dias Costa, Jonathan A Nowak, Brian M Wolpin, Robert H Vonderheide, Jeremy Goecks, Lisa M Coussens, Katelyn T Byrne
Tumor molecular data sets are becoming increasingly complex, making it nearly impossible for humans alone to effectively analyze them. Here, we demonstrate the power of using machine learning (ML) to analyze a single-cell, spatial, and highly multiplexed proteomic data set from human pancreatic cancer and reveal underlying biological mechanisms that may contribute to clinical outcomes. We designed a multiplex immunohistochemistry antibody panel to compare T-cell functionality and spatial localization in resected tumors from treatment-naïve patients with localized pancreatic ductal adenocarcinoma (PDAC) with resected tumors from a second cohort of patients treated with neoadjuvant agonistic CD40 (anti-CD40) monoclonal antibody therapy. In total, nearly 2.5 million cells from 306 tissue regions collected from 29 patients across both cohorts were assayed, and over 1,000 tumor microenvironment (TME) features were quantified. We then trained ML models to accurately predict anti-CD40 treatment status and disease-free survival (DFS) following anti-CD40 therapy based on TME features. Through downstream interpretation of the ML models' predictions, we found anti-CD40 therapy reduced canonical aspects of T-cell exhaustion within the TME, as compared with treatment-naïve TMEs. Using automated clustering approaches, we found improved DFS following anti-CD40 therapy correlated with an increased presence of CD44+CD4+ Th1 cells located specifically within cellular neighborhoods characterized by increased T-cell proliferation, antigen experience, and cytotoxicity in immune aggregates. Overall, our results demonstrate the utility of ML in molecular cancer immunology applications, highlight the impact of anti-CD40 therapy on T cells within the TME, and identify potential candidate biomarkers of DFS for anti-CD40-treated patients with PDAC.
肿瘤分子数据集正变得越来越复杂,单靠人类几乎不可能对其进行有效分析。在这里,我们展示了使用机器学习(ML)分析人类胰腺癌单细胞、空间和高度多重蛋白组数据集的能力,并揭示了可能有助于临床结果的潜在生物机制。我们设计了一个多重免疫组化抗体面板,用于比较局部胰腺导管腺癌(PDAC)治疗无效患者切除肿瘤中的T细胞功能和空间定位,以及接受新辅助激动剂CD40(抗CD40)单克隆抗体治疗的第二组患者切除肿瘤中的T细胞功能和空间定位。我们总共检测了来自两个队列中 29 位患者的 306 个组织区域的近 250 万个细胞,并量化了 1,000 多个肿瘤微环境 (TME) 特征。然后,我们对 ML 模型进行了训练,以根据 TME 特征准确预测抗 CD40 治疗状态和抗 CD40 治疗后的无病生存期 (DFS)。通过对 ML 模型预测的下游解释,我们发现与未接受治疗的 TME 相比,抗 CD40 治疗减少了 TME 内 T 细胞衰竭的典型方面。利用自动聚类方法,我们发现抗 CD40 治疗后 DFS 的改善与 CD44+CD4+ Th1 细胞的增加有关,这些细胞特异性地位于细胞邻域内,其特点是 T 细胞增殖、抗原经验和免疫聚集体的细胞毒性增加。总之,我们的研究结果证明了 ML 在分子癌症免疫学应用中的实用性,强调了抗 CD40 治疗对 TME 内 T 细胞的影响,并确定了抗 CD40 治疗的 PDAC 患者 DFS 的潜在候选生物标记物。
{"title":"Machine Learning Links T-cell Function and Spatial Localization to Neoadjuvant Immunotherapy and Clinical Outcome in Pancreatic Cancer.","authors":"Katie E Blise, Shamilene Sivagnanam, Courtney B Betts, Konjit Betre, Nell Kirchberger, Benjamin J Tate, Emma E Furth, Andressa Dias Costa, Jonathan A Nowak, Brian M Wolpin, Robert H Vonderheide, Jeremy Goecks, Lisa M Coussens, Katelyn T Byrne","doi":"10.1158/2326-6066.CIR-23-0873","DOIUrl":"10.1158/2326-6066.CIR-23-0873","url":null,"abstract":"<p><p>Tumor molecular data sets are becoming increasingly complex, making it nearly impossible for humans alone to effectively analyze them. Here, we demonstrate the power of using machine learning (ML) to analyze a single-cell, spatial, and highly multiplexed proteomic data set from human pancreatic cancer and reveal underlying biological mechanisms that may contribute to clinical outcomes. We designed a multiplex immunohistochemistry antibody panel to compare T-cell functionality and spatial localization in resected tumors from treatment-naïve patients with localized pancreatic ductal adenocarcinoma (PDAC) with resected tumors from a second cohort of patients treated with neoadjuvant agonistic CD40 (anti-CD40) monoclonal antibody therapy. In total, nearly 2.5 million cells from 306 tissue regions collected from 29 patients across both cohorts were assayed, and over 1,000 tumor microenvironment (TME) features were quantified. We then trained ML models to accurately predict anti-CD40 treatment status and disease-free survival (DFS) following anti-CD40 therapy based on TME features. Through downstream interpretation of the ML models' predictions, we found anti-CD40 therapy reduced canonical aspects of T-cell exhaustion within the TME, as compared with treatment-naïve TMEs. Using automated clustering approaches, we found improved DFS following anti-CD40 therapy correlated with an increased presence of CD44+CD4+ Th1 cells located specifically within cellular neighborhoods characterized by increased T-cell proliferation, antigen experience, and cytotoxicity in immune aggregates. Overall, our results demonstrate the utility of ML in molecular cancer immunology applications, highlight the impact of anti-CD40 therapy on T cells within the TME, and identify potential candidate biomarkers of DFS for anti-CD40-treated patients with PDAC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11065586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139912087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-02DOI: 10.1158/2326-6066.CIR-23-0568
Jane Tian, Amir M Ashique, Sabrina Weeks, Tian Lan, Hong Yang, Hung-I Harry Chen, Christina Song, Kikuye Koyano, Kalyani Mondal, Daniel Tsai, Isla Cheung, Mehrdad Moshrefi, Avantika Kekatpure, Bin Fan, Betty Li, Samir Qurashi, Lauren Rocha, Jonathan Aguayo, Col Rodgers, Marchelle Meza, Darren Heeke, Sara M Medfisch, Chun Chu, Shelley Starck, Nandini Pal Basak, Satish Sankaran, Mohit Malhotra, Suzanne Crawley, Thomas-Toan Tran, Dana Y Duey, Carmence Ho, Igor Mikaelian, Wenhui Liu, Lee B Rivera, Jiawei Huang, Kevin J Paavola, Kyle O'Hollaren, Lisa K Blum, Vicky Y Lin, Peirong Chen, Anjushree Iyer, Sisi He, Julie M Roda, Yan Wang, James Sissons, Alan K Kutach, Daniel D Kaplan, Geoffrey W Stone
Solid tumors are dense three-dimensional (3D) multicellular structures that enable efficient receptor-ligand trans interactions via close cell-cell contact. Immunoglobulin-like transcript (ILT)2 and ILT4 are related immune-suppressive receptors that play a role in the inhibition of myeloid cells within the tumor microenvironment. The relative contribution of ILT2 and ILT4 to immune inhibition in the context of solid tumor tissue has not been fully explored. We present evidence that both ILT2 and ILT4 contribute to myeloid inhibition. We found that although ILT2 inhibits myeloid cell activation in the context of trans-engagement by MHC-I, ILT4 efficiently inhibits myeloid cells in the presence of either cis- or trans-engagement. In a 3D spheroid tumor model, dual ILT2/ILT4 blockade was required for the optimal activation of myeloid cells, including the secretion of CXCL9 and CCL5, upregulation of CD86 on dendritic cells, and downregulation of CD163 on macrophages. Humanized mouse tumor models showed increased immune activation and cytolytic T-cell activity with combined ILT2 and ILT4 blockade, including evidence of the generation of immune niches, which have been shown to correlate with clinical response to immune-checkpoint blockade. In a human tumor explant histoculture system, dual ILT2/ILT4 blockade increased CXCL9 secretion, downregulated CD163 expression, and increased the expression of M1 macrophage, IFNγ, and cytolytic T-cell gene signatures. Thus, we have revealed distinct contributions of ILT2 and ILT4 to myeloid cell biology and provide proof-of-concept data supporting the combined blockade of ILT2 and ILT4 to therapeutically induce optimal myeloid cell reprogramming in the tumor microenvironment.
{"title":"ILT2 and ILT4 Drive Myeloid Suppression via Both Overlapping and Distinct Mechanisms.","authors":"Jane Tian, Amir M Ashique, Sabrina Weeks, Tian Lan, Hong Yang, Hung-I Harry Chen, Christina Song, Kikuye Koyano, Kalyani Mondal, Daniel Tsai, Isla Cheung, Mehrdad Moshrefi, Avantika Kekatpure, Bin Fan, Betty Li, Samir Qurashi, Lauren Rocha, Jonathan Aguayo, Col Rodgers, Marchelle Meza, Darren Heeke, Sara M Medfisch, Chun Chu, Shelley Starck, Nandini Pal Basak, Satish Sankaran, Mohit Malhotra, Suzanne Crawley, Thomas-Toan Tran, Dana Y Duey, Carmence Ho, Igor Mikaelian, Wenhui Liu, Lee B Rivera, Jiawei Huang, Kevin J Paavola, Kyle O'Hollaren, Lisa K Blum, Vicky Y Lin, Peirong Chen, Anjushree Iyer, Sisi He, Julie M Roda, Yan Wang, James Sissons, Alan K Kutach, Daniel D Kaplan, Geoffrey W Stone","doi":"10.1158/2326-6066.CIR-23-0568","DOIUrl":"10.1158/2326-6066.CIR-23-0568","url":null,"abstract":"<p><p>Solid tumors are dense three-dimensional (3D) multicellular structures that enable efficient receptor-ligand trans interactions via close cell-cell contact. Immunoglobulin-like transcript (ILT)2 and ILT4 are related immune-suppressive receptors that play a role in the inhibition of myeloid cells within the tumor microenvironment. The relative contribution of ILT2 and ILT4 to immune inhibition in the context of solid tumor tissue has not been fully explored. We present evidence that both ILT2 and ILT4 contribute to myeloid inhibition. We found that although ILT2 inhibits myeloid cell activation in the context of trans-engagement by MHC-I, ILT4 efficiently inhibits myeloid cells in the presence of either cis- or trans-engagement. In a 3D spheroid tumor model, dual ILT2/ILT4 blockade was required for the optimal activation of myeloid cells, including the secretion of CXCL9 and CCL5, upregulation of CD86 on dendritic cells, and downregulation of CD163 on macrophages. Humanized mouse tumor models showed increased immune activation and cytolytic T-cell activity with combined ILT2 and ILT4 blockade, including evidence of the generation of immune niches, which have been shown to correlate with clinical response to immune-checkpoint blockade. In a human tumor explant histoculture system, dual ILT2/ILT4 blockade increased CXCL9 secretion, downregulated CD163 expression, and increased the expression of M1 macrophage, IFNγ, and cytolytic T-cell gene signatures. Thus, we have revealed distinct contributions of ILT2 and ILT4 to myeloid cell biology and provide proof-of-concept data supporting the combined blockade of ILT2 and ILT4 to therapeutically induce optimal myeloid cell reprogramming in the tumor microenvironment.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139939739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tumor-associated macrophages (TAM) induce immunosuppression in laryngeal squamous cell carcinoma (LSCC). The interaction between LSCC cells and TAMs affects the progression of laryngeal cancer through exosomes, but the underlying molecular mechanism remains unclear. Proteomics analysis of TAMs isolated from human laryngeal tumor tissues obtained from patients with confirmed lymphatic metastasis revealed an upregulation of annexin A3 (ANXA3). In TAMs, ANXA3 promoted macrophages to polarize to an M2-like phenotype by activating the AKT-GSK3β-β-catenin pathway. In addition, ANXA3-rich exosomes derived from TAMs inhibited ferroptosis in laryngeal cancer cells through an ATF2-CHAC1 axis, and this process was associated with lymphatic metastasis. Mechanistically, ANXA3 in exosomes inhibited the ubiquitination of ATF2, whereas ATF2 acted as a transcription factor to regulate the expression of CHAC1, thus inhibiting ferroptosis in LSCC cells. These data indicate that abnormal ANXA3 expression can drive TAM reprogramming and promote an immunosuppressive microenvironment in LSCC. Meanwhile, ANXA3-rich exosomes inhibit ferroptosis of LSCC cells and promote lymphatic metastasis, thus promoting tumor progression.
{"title":"ANXA3-Rich Exosomes Derived from Tumor-Associated Macrophages Regulate Ferroptosis and Lymphatic Metastasis of Laryngeal Squamous Cell Carcinoma.","authors":"Licheng Xu, Wenjing Li, Danxi Liu, Jing Cao, Jingchun Ge, Xinyu Liu, Yue Wang, Yujian Teng, Pengyan Liu, Xinyue Guo, Chen He, Ming Liu, Linli Tian","doi":"10.1158/2326-6066.CIR-23-0595","DOIUrl":"10.1158/2326-6066.CIR-23-0595","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAM) induce immunosuppression in laryngeal squamous cell carcinoma (LSCC). The interaction between LSCC cells and TAMs affects the progression of laryngeal cancer through exosomes, but the underlying molecular mechanism remains unclear. Proteomics analysis of TAMs isolated from human laryngeal tumor tissues obtained from patients with confirmed lymphatic metastasis revealed an upregulation of annexin A3 (ANXA3). In TAMs, ANXA3 promoted macrophages to polarize to an M2-like phenotype by activating the AKT-GSK3β-β-catenin pathway. In addition, ANXA3-rich exosomes derived from TAMs inhibited ferroptosis in laryngeal cancer cells through an ATF2-CHAC1 axis, and this process was associated with lymphatic metastasis. Mechanistically, ANXA3 in exosomes inhibited the ubiquitination of ATF2, whereas ATF2 acted as a transcription factor to regulate the expression of CHAC1, thus inhibiting ferroptosis in LSCC cells. These data indicate that abnormal ANXA3 expression can drive TAM reprogramming and promote an immunosuppressive microenvironment in LSCC. Meanwhile, ANXA3-rich exosomes inhibit ferroptosis of LSCC cells and promote lymphatic metastasis, thus promoting tumor progression.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139939738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-02DOI: 10.1158/2326-6066.CIR-12-5-WWR
{"title":"A Sampling of Highlights from the Literature.","authors":"","doi":"10.1158/2326-6066.CIR-12-5-WWR","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-12-5-WWR","url":null,"abstract":"","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140847954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chimeric antigen receptor (CAR) T cells are emerging as an effective antitumoral therapy. However, their therapeutic effects on solid tumors are limited because of their short survival time and the immunosuppressive tumor microenvironment. Memory T cells respond more vigorously and persist longer than their naïve/effector counterparts. Therefore, promoting CAR T-cell development into memory T cells could further enhance their antitumoral effects. HI-TOPK-032 is a T-LAK cell-originated protein kinase (TOPK)-specific inhibitor that moderately represses some types of tumors. However, it is unknown whether HI-TOPK-032 works on hepatocellular carcinoma (HCC) and whether it impacts antitumoral immunity. Using both subcutaneous and orthotopic xenograft tumor models of two human HCC cell lines, Huh-7 and HepG2, we found that HI-TOPK-032 significantly improved proliferation/persistence of CD8+ CAR T cells, as evidenced by an increase in CAR T-cell counts or frequency of Ki-67+CD8+ cells and a decrease in PD-1+LAG-3+TIM-3+CD8+ CAR T cells in vivo. Although HI-TOPK-032 did not significantly suppress HCC growth, it enhanced the capacity of CAR T cells to inhibit tumor growth. Moreover, HI-TOPK-032 augmented central memory CD8+ T cell (TCM) frequency while increasing eomesodermin expression in CD8+ CAR T cells in tumor-bearing mice. Moreover, it augmented CD8+ CAR TCM cells in vitro and reduced their expression of immune checkpoint molecules. Finally, HI-TOPK-032 inhibited mTOR activation in CAR T cells in vitro and in tumors, whereas overactivation of mTOR reversed the effects of HI-TOPK-032 on CD8+ TCM cells and tumor growth. Thus, our studies have revealed mechanisms underlying the antitumoral effects of HI-TOPK-032 while advancing CAR T-cell immunotherapy.
嵌合抗原受体(CAR)T细胞正在成为一种有效的抗肿瘤疗法。然而,由于肿瘤存活时间短以及肿瘤微环境的免疫抑制作用,它们对实体瘤的治疗效果有限。与天真/效应细胞相比,记忆 T 细胞的反应更强烈,存活时间更长。因此,促进 CAR T 细胞向记忆 T 细胞发展可进一步增强其抗肿瘤效果。HI-TOPK-032是一种TOPK特异性抑制剂,可中度抑制某些类型的肿瘤。然而,HI-TOPK-032 是否对肝细胞癌(HCC)起作用以及是否会影响抗肿瘤免疫尚不清楚。通过使用两种人类 HCC 细胞系 Huh-7 和 HepG2 的皮下和正位异种移植肿瘤模型,我们发现 HI-TOPK-032 能显著改善 CD8+ CAR T 细胞的增殖/存活,表现为体内 CAR T 细胞数量或 Ki-67+CD8+ 细胞频率的增加以及 PD-1+LAG-3+TIM-3+CD8+ CAR T 细胞数量的减少。虽然HI-TOPK-032没有明显抑制HCC的生长,但它增强了CAR T细胞抑制肿瘤生长的能力。此外,HI-TOPK-032还提高了肿瘤小鼠体内CD8+ CAR T细胞的中枢记忆CD8+ T细胞(TCM)频率,同时增加了CD8+ CAR T细胞中eomesodermin的表达。此外,HI-TOPK-032 还能增强体外的 CD8+ CAR TCM 细胞,并减少其免疫检查点分子的表达。最后,HI-TOPK-032 抑制了体外和肿瘤中 CAR T 细胞的 mTOR 激活,而 mTOR 的过度激活则逆转了 HI-TOPK-032 对 CD8+ 中医细胞和肿瘤生长的影响。因此,我们的研究揭示了HI-TOPK-032抗肿瘤作用的机制,同时推动了CAR T细胞免疫疗法的发展。
{"title":"The TOPK Inhibitor HI-TOPK-032 Enhances CAR T-cell Therapy of Hepatocellular Carcinoma by Upregulating Memory T Cells.","authors":"Qunfang Zhang, Fang Zheng, Yuchao Chen, Chun-Ling Liang, Huazhen Liu, Feifei Qiu, Yunshan Liu, Hongfeng Huang, Weihui Lu, Zhenhua Dai","doi":"10.1158/2326-6066.CIR-23-0587","DOIUrl":"10.1158/2326-6066.CIR-23-0587","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cells are emerging as an effective antitumoral therapy. However, their therapeutic effects on solid tumors are limited because of their short survival time and the immunosuppressive tumor microenvironment. Memory T cells respond more vigorously and persist longer than their naïve/effector counterparts. Therefore, promoting CAR T-cell development into memory T cells could further enhance their antitumoral effects. HI-TOPK-032 is a T-LAK cell-originated protein kinase (TOPK)-specific inhibitor that moderately represses some types of tumors. However, it is unknown whether HI-TOPK-032 works on hepatocellular carcinoma (HCC) and whether it impacts antitumoral immunity. Using both subcutaneous and orthotopic xenograft tumor models of two human HCC cell lines, Huh-7 and HepG2, we found that HI-TOPK-032 significantly improved proliferation/persistence of CD8+ CAR T cells, as evidenced by an increase in CAR T-cell counts or frequency of Ki-67+CD8+ cells and a decrease in PD-1+LAG-3+TIM-3+CD8+ CAR T cells in vivo. Although HI-TOPK-032 did not significantly suppress HCC growth, it enhanced the capacity of CAR T cells to inhibit tumor growth. Moreover, HI-TOPK-032 augmented central memory CD8+ T cell (TCM) frequency while increasing eomesodermin expression in CD8+ CAR T cells in tumor-bearing mice. Moreover, it augmented CD8+ CAR TCM cells in vitro and reduced their expression of immune checkpoint molecules. Finally, HI-TOPK-032 inhibited mTOR activation in CAR T cells in vitro and in tumors, whereas overactivation of mTOR reversed the effects of HI-TOPK-032 on CD8+ TCM cells and tumor growth. Thus, our studies have revealed mechanisms underlying the antitumoral effects of HI-TOPK-032 while advancing CAR T-cell immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139971037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-02DOI: 10.1158/2326-6066.CIR-23-0378
Xu Wang, Long Zhang, Yi Zhou, Yan Wang, Xiang Wang, Yining Zhang, Ankang Quan, Yufei Mao, Yu Zhang, Ji Qi, Zhongyu Ren, Linbo Gu, Rutong Yu, Xiuping Zhou
As understanding of cancer has deepened, increasing attention has been turned to the roles of psychological factors, especially chronic stress-induced depression, in the occurrence and development of tumors. However, whether and how depression affects the progression of gliomas are still unclear. In this study, we have revealed that chronic stress inhibited the recruitment of tumor-associated macrophages (TAM) and other immune cells, especially M1-type TAMs and CD8+ T cells, and decreased the level of proinflammatory cytokines in gliomas, leading to an immunosuppressive microenvironment and glioma progression. Mechanistically, by promoting the secretion of stress hormones, chronic stress inhibited the secretion of the chemokine CCL3 and the recruitment of M1-type TAMs in gliomas. Intratumoral administration of CCL3 reprogrammed the immune microenvironment of gliomas and abolished the progression of gliomas induced by chronic stress. Moreover, levels of CCL3 and M1-type TAMs were decreased in the tumor tissues of glioma patients with depression, and CCL3 administration enhanced the antitumor effect of anti-PD-1 therapy in orthotopic models of gliomas undergoing chronic stress. In conclusion, our study has revealed that chronic stress exacerbates the immunosuppressive microenvironment and progression of gliomas by reducing the secretion of CCL3. CCL3 alone or in combination with an anti-PD-1 may be an effective immunotherapy for the treatment of gliomas with depression. See related Spotlight by Cui and Kang, p. 514.
{"title":"Chronic Stress Exacerbates the Immunosuppressive Microenvironment and Progression of Gliomas by Reducing Secretion of CCL3.","authors":"Xu Wang, Long Zhang, Yi Zhou, Yan Wang, Xiang Wang, Yining Zhang, Ankang Quan, Yufei Mao, Yu Zhang, Ji Qi, Zhongyu Ren, Linbo Gu, Rutong Yu, Xiuping Zhou","doi":"10.1158/2326-6066.CIR-23-0378","DOIUrl":"10.1158/2326-6066.CIR-23-0378","url":null,"abstract":"<p><p>As understanding of cancer has deepened, increasing attention has been turned to the roles of psychological factors, especially chronic stress-induced depression, in the occurrence and development of tumors. However, whether and how depression affects the progression of gliomas are still unclear. In this study, we have revealed that chronic stress inhibited the recruitment of tumor-associated macrophages (TAM) and other immune cells, especially M1-type TAMs and CD8+ T cells, and decreased the level of proinflammatory cytokines in gliomas, leading to an immunosuppressive microenvironment and glioma progression. Mechanistically, by promoting the secretion of stress hormones, chronic stress inhibited the secretion of the chemokine CCL3 and the recruitment of M1-type TAMs in gliomas. Intratumoral administration of CCL3 reprogrammed the immune microenvironment of gliomas and abolished the progression of gliomas induced by chronic stress. Moreover, levels of CCL3 and M1-type TAMs were decreased in the tumor tissues of glioma patients with depression, and CCL3 administration enhanced the antitumor effect of anti-PD-1 therapy in orthotopic models of gliomas undergoing chronic stress. In conclusion, our study has revealed that chronic stress exacerbates the immunosuppressive microenvironment and progression of gliomas by reducing the secretion of CCL3. CCL3 alone or in combination with an anti-PD-1 may be an effective immunotherapy for the treatment of gliomas with depression. See related Spotlight by Cui and Kang, p. 514.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140027436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}