Cancer immunology research最新文献_第10页

Knocking Out CD70 Rescues CD70-Specific NanoCAR T Cells from Antigen-Induced Exhaustion. 敲除 CD70 可使 CD70 特异性 nanoCAR T 细胞从抗原诱导的衰竭中解救出来。

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-09-03 DOI: 10.1158/2326-6066.CIR-23-0677

Stijn De Munter, Juliane L Buhl, Laurenz De Cock, Alexander Van Parys, Willem Daneels, Eva Pascal, Lucas Deseins, Joline Ingels, Glenn Goetgeluk, Hanne Jansen, Lore Billiet, Melissa Pille, Julie Van Duyse, Sarah Bonte, Niels Vandamme, Jo Van Dorpe, Fritz Offner, Georges Leclercq, Tom Taghon, Erik Depla, Jan Tavernier, Tessa Kerre, Jarno Drost, Bart Vandekerckhove

{"title":"Knocking Out CD70 Rescues CD70-Specific NanoCAR T Cells from Antigen-Induced Exhaustion.","authors":"Stijn De Munter, Juliane L Buhl, Laurenz De Cock, Alexander Van Parys, Willem Daneels, Eva Pascal, Lucas Deseins, Joline Ingels, Glenn Goetgeluk, Hanne Jansen, Lore Billiet, Melissa Pille, Julie Van Duyse, Sarah Bonte, Niels Vandamme, Jo Van Dorpe, Fritz Offner, Georges Leclercq, Tom Taghon, Erik Depla, Jan Tavernier, Tessa Kerre, Jarno Drost, Bart Vandekerckhove","doi":"10.1158/2326-6066.CIR-23-0677","DOIUrl":"10.1158/2326-6066.CIR-23-0677","url":null,"abstract":"CD70 is an attractive target for chimeric antigen receptor (CAR) T-cell therapy for the treatment of both solid and liquid malignancies. However, the functionality of CD70-specific CAR T cells is modest. We optimized a CD70-specific VHH-based CAR (nanoCAR). We evaluated the nanoCARs in clinically relevant models in vitro, using co-cultures of CD70-specific nanoCAR T cells with malignant rhabdoid tumor organoids, and in vivo, using a diffuse large B-cell lymphoma patient-derived xenograft (PDX) model. Although the nanoCAR T cells were highly efficient in organoid co-cultures, they showed only modest efficacy in the PDX model. We determined that fratricide was not causing this loss in efficacy but rather CD70 interaction in cis with the nanoCAR-induced exhaustion. Knocking out CD70 in nanoCAR T cells using CRISPR/Cas9 resulted in dramatically enhanced functionality in the diffuse large B-cell lymphoma PDX model. Through single-cell transcriptomics, we obtained evidence that CD70 knockout CD70-specific nanoCAR T cells were protected from antigen-induced exhaustion. In addition, we demonstrated that wild-type CD70-specific nanoCAR T cells already exhibited signs of exhaustion shortly after production. Their gene signature strongly overlapped with gene signatures of exhausted CAR T cells. Conversely, the gene signature of knockout CD70-specific nanoCAR T cells overlapped with the gene signature of CAR T-cell infusion products leading to complete responses in chronic lymphatic leukemia patients. Our data show that CARs targeting endogenous T-cell antigens negatively affect CAR T-cell functionality by inducing an exhausted state, which can be overcome by knocking out the specific target.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1236-1251"},"PeriodicalIF":8.1,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316752","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}

引用次数: 0

A Sampling of Highlights from the Literature. 文献精华选集》。

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-09-03 DOI: 10.1158/2326-6066.CIR-12-9-WWR

引用次数: 0

Improvement of Tumor Neoantigen Detection by High-Field Asymmetric Waveform Ion Mobility Mass Spectrometry. 利用高场非对称波形离子迁移质谱改进肿瘤新抗原的检测。

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-08-01 DOI: 10.1158/2326-6066.CIR-23-0900

Wei Meng, Yoshiko Takeuchi, Jeffrey P Ward, Hussein Sultan, Cora D Arthur, Elaine R Mardis, Maxim N Artyomov, Cheryl F Lichti, Robert D Schreiber

{"title":"Improvement of Tumor Neoantigen Detection by High-Field Asymmetric Waveform Ion Mobility Mass Spectrometry.","authors":"Wei Meng, Yoshiko Takeuchi, Jeffrey P Ward, Hussein Sultan, Cora D Arthur, Elaine R Mardis, Maxim N Artyomov, Cheryl F Lichti, Robert D Schreiber","doi":"10.1158/2326-6066.CIR-23-0900","DOIUrl":"10.1158/2326-6066.CIR-23-0900","url":null,"abstract":"Cancer neoantigens have been shown to elicit cancer-specific T-cell responses and have garnered much attention for their roles in both spontaneous and therapeutically induced antitumor responses. Mass spectrometry (MS) profiling of tumor immunopeptidomes has been used, in part, to identify MHC-bound mutant neoantigen ligands. However, under standard conditions, MS-based detection of such rare but clinically relevant neoantigens is relatively insensitive, requiring 300 million cells or more. Here, to quantitatively define the minimum detectable amounts of therapeutically relevant MHC-I and MHC-II neoantigen peptides, we analyzed different dilutions of immunopeptidomes isolated from the well-characterized T3 mouse methylcholanthrene (MCA)-induced cell line by MS. Using either data-dependent acquisition or parallel reaction monitoring (PRM), we established the minimum amount of material required to detect the major T3 neoantigens in the presence or absence of high field asymmetric waveform ion mobility spectrometry (FAIMS). This analysis yielded a 14-fold enhancement of sensitivity in detecting the major T3 MHC-I neoantigen (mLama4) with FAIMS-PRM compared with PRM without FAIMS, allowing ex vivo detection of this neoantigen from an individual 100 mg T3 tumor. These findings were then extended to two other independent MCA-sarcoma lines (1956 and F244). This study demonstrates that FAIMS substantially increases the sensitivity of MS-based characterization of validated neoantigens from tumors.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"988-1006"},"PeriodicalIF":8.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070553","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}

引用次数: 0

"Couple's Immunotherapy": Is CXCL13 at the Heart of the Prescription? "夫妻免疫疗法"：CXCL13 是处方的核心吗？

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-08-01 DOI: 10.1158/2326-6066.CIR-24-0481

Eduardo Cruz-Hinojoza, Ingunn M Stromnes

引用次数: 0

A Sampling of Highlights from the Literature. 文献精华选集》。

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-08-01 DOI: 10.1158/2326-6066.CIR-12-8-WWR

引用次数: 0

CLN-617 Retains IL2 and IL12 in Injected Tumors to Drive Robust and Systemic Immune-Mediated Antitumor Activity. CLN-617 可在注射的肿瘤中保留 IL-2 和 IL-12，从而产生强大的全身免疫介导抗肿瘤活性。

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-08-01 DOI: 10.1158/2326-6066.CIR-23-0636

Naveen K Mehta, Kavya Rakhra, Kristan A Meetze, Bochong Li, Noor Momin, Jason Y H Chang, K Dane Wittrup, Patrick A Baeuerle, Jennifer S Michaelson

{"title":"CLN-617 Retains IL2 and IL12 in Injected Tumors to Drive Robust and Systemic Immune-Mediated Antitumor Activity.","authors":"Naveen K Mehta, Kavya Rakhra, Kristan A Meetze, Bochong Li, Noor Momin, Jason Y H Chang, K Dane Wittrup, Patrick A Baeuerle, Jennifer S Michaelson","doi":"10.1158/2326-6066.CIR-23-0636","DOIUrl":"10.1158/2326-6066.CIR-23-0636","url":null,"abstract":"Despite clinical evidence of antitumor activity, the development of cytokine therapies has been hampered by a narrow therapeutic window and limited response rates. Two cytokines of high interest for clinical development are interleukin 2 (IL2) and interleukin 12 (IL12), which potently synergize to promote the activation and proliferation of T cells and NK cells. However, the only approved human IL2 therapy, Proleukin, is rarely used in the clinic due to systemic toxicities, and no IL12 product has been approved to date due to severe dose-limiting toxicities. Here, we describe CLN-617, a first-in-class therapeutic for intratumoral (IT) injection that co-delivers IL2 and IL12 on a single molecule in a safe and effective manner. CLN-617 is a single-chain fusion protein comprised of IL2, leukocyte-associated immunoglobulin-like receptor 2 (LAIR2), human serum albumin (HSA), and IL12. LAIR2 and HSA function to retain CLN-617 in the treated tumor by binding collagen and increasing molecular weight, respectively. We found that IT administration of a murine surrogate of CLN-617, mCLN-617, eradicated established treated and untreated tumors in syngeneic models, significantly improved response to anti-PD1 checkpoint therapy, and generated a robust abscopal response dependent on cellular immunity and antigen cross-presentation. CLN-617 is being evaluated in a clinical trial in patients with advanced solid tumors (NCT06035744).","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1022-1038"},"PeriodicalIF":8.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11292205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261118","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}

引用次数: 0

Venetoclax Induces BCL-2-Dependent Treg to TH17 Plasticity to Enhance the Antitumor Efficacy of Anti-PD-1 Checkpoint Blockade. Venetoclax诱导BCL-2依赖性Treg到TH17的可塑性，从而增强抗PD-1检查点阻断的抗肿瘤疗效。

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-08-01 DOI: 10.1158/2326-6066.CIR-23-0344

Rosy Liao, Jocelyn Y Hsu, Nada S Aboelella, Joshua A McKeever, Anika T Thomas-Toth, Andrew S Koh, James L LaBelle

{"title":"Venetoclax Induces BCL-2-Dependent Treg to TH17 Plasticity to Enhance the Antitumor Efficacy of Anti-PD-1 Checkpoint Blockade.","authors":"Rosy Liao, Jocelyn Y Hsu, Nada S Aboelella, Joshua A McKeever, Anika T Thomas-Toth, Andrew S Koh, James L LaBelle","doi":"10.1158/2326-6066.CIR-23-0344","DOIUrl":"10.1158/2326-6066.CIR-23-0344","url":null,"abstract":"The specific BCL-2 small molecule inhibitor venetoclax induces apoptosis in a wide range of malignancies, which has led to rapid clinical expansion in its use alone and in combination with chemotherapy and immune-based therapies against a myriad of cancer types. While lymphocytes, and T cells in particular, rely heavily on BCL-2 for survival and function, the effects of small molecule blockade of the BCL-2 family on surviving immune cells is not fully understood. We aimed to better understand the effect of systemic treatment with venetoclax on regulatory T cells (Treg), which are relatively resistant to cell death induced by specific drugging of BCL-2 compared to other T cells. We found that BCL-2 blockade altered Treg transcriptional profiles and mediated Treg plasticity toward a TH17-like Treg phenotype, resulting in increased IL17A production in lymphoid organs and within the tumor microenvironment. Aligned with previously described augmented antitumor effects observed when combining venetoclax with anti-PD-1 checkpoint inhibition, we also demonstrated that Treg-specific genetic BCL-2 knockout combined with anti-PD-1 induced tumor regression and conferred overlapping genetic changes with venetoclax-treated Tregs. As long-term combination therapies using venetoclax gain more traction in the clinic, an improved understanding of the immune-modulatory effects caused by venetoclax may allow expansion of its use against malignancies and immune-related diseases.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1074-1089"},"PeriodicalIF":8.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174870","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}

引用次数: 0

Low Serum Apolipoprotein A1 Levels Impair Antitumor Immunity of CD8+ T Cells via the HIF-1α-Glycolysis Pathway. 低血清载脂蛋白 A1 通过 HIF-1α 糖酵解途径损害 CD8+ T 细胞的抗肿瘤免疫力

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-08-01 DOI: 10.1158/2326-6066.CIR-23-0506

Qiaoying Lv, Tong Su, Wei Liu, Lulu Wang, Jiali Hu, Yali Cheng, Chengcheng Ning, Weiwei Shan, Xuezhen Luo, Xiaojun Chen

{"title":"Low Serum Apolipoprotein A1 Levels Impair Antitumor Immunity of CD8+ T Cells via the HIF-1α-Glycolysis Pathway.","authors":"Qiaoying Lv, Tong Su, Wei Liu, Lulu Wang, Jiali Hu, Yali Cheng, Chengcheng Ning, Weiwei Shan, Xuezhen Luo, Xiaojun Chen","doi":"10.1158/2326-6066.CIR-23-0506","DOIUrl":"10.1158/2326-6066.CIR-23-0506","url":null,"abstract":"An immunosuppressive microenvironment promotes the occurrence and development of tumors. Low apolipoprotein A1 (ApoA1) is closely related to tumor development, but the underlying mechanisms are unclear. This study investigated the association between serum ApoA1 levels and the immune microenvironment in endometrial, ovarian, and lung cancers. The serum ApoA1 level was decreased significantly in patients with endometrial and ovarian cancers compared with healthy controls. In endometrial cancer (EC) tissues, the low serum ApoA1 level group showed increased CD163+ macrophage infiltration and decreased CD8+ T-cell infiltration compared with the normal serum ApoA1 group. Compromised tumor-infiltrating CD8+ T-cell functions and decreased CD8+ T-cell infiltration also were found in tumor-bearing Apo1-knockout mice. CD8+ T-cell depletion experiments confirmed that ApoA1 exerted its antitumor activity in a CD8+ T-cell-dependent manner. In vitro experiments showed that the ApoA1 mimetic peptide L-4F directly potentiated the antitumor activity of CD8+ T cells via a HIF-1α-mediated glycolysis pathway. Mechanistically, ApoA1 suppressed ubiquitin-mediated degradation of HIF-1α protein by downregulating HIF-1α subunit α inhibitor. This regulatory process maintained the stability of HIF-1α protein and activated the HIF-1α signaling pathway. Tumor-bearing Apoa1 transgenic mice showed an increased response to anti-PD-1 therapy, leading to reduced tumor growth along with increased infiltration of activated CD8+ T cells and enhanced tumor necrosis. The data reported herein demonstrate critical roles for ApoA1 in enhancing CD8+ T-cell immune functions via HIF-1α-mediated glycolysis and support clinical investigation of combining ApoA1 supplementation with anti-PD-1 therapy for treating cancer.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1058-1073"},"PeriodicalIF":8.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944096","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}

引用次数: 0

Molecular Pathways and Cellular Subsets Associated with Adverse Clinical Outcomes in Overlapping Immune-Related Myocarditis and Myositis. 与重叠性免疫相关心肌炎和肌炎不良临床结果相关的分子途径和细胞亚群。

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-08-01 DOI: 10.1158/2326-6066.CIR-24-0011

Bilal A Siddiqui, Nicolas L Palaskas, Sreyashi Basu, Yibo Dai, Zhong He, Shalini S Yadav, James P Allison, Rahul A Sheth, Sudhakar Tummala, Maximilian Buja, Meenakshi B Bhattacharjee, Cezar Iliescu, Anishia Rawther-Karedath, Anita Deswal, Linghua Wang, Padmanee Sharma, Sumit K Subudhi

{"title":"Molecular Pathways and Cellular Subsets Associated with Adverse Clinical Outcomes in Overlapping Immune-Related Myocarditis and Myositis.","authors":"Bilal A Siddiqui, Nicolas L Palaskas, Sreyashi Basu, Yibo Dai, Zhong He, Shalini S Yadav, James P Allison, Rahul A Sheth, Sudhakar Tummala, Maximilian Buja, Meenakshi B Bhattacharjee, Cezar Iliescu, Anishia Rawther-Karedath, Anita Deswal, Linghua Wang, Padmanee Sharma, Sumit K Subudhi","doi":"10.1158/2326-6066.CIR-24-0011","DOIUrl":"10.1158/2326-6066.CIR-24-0011","url":null,"abstract":"Immune checkpoint therapies (ICT) can induce life-threatening immune-related adverse events, including myocarditis and myositis, which are rare but often concurrent. The molecular pathways and immune subsets underlying these toxicities remain poorly understood. To address this need, we performed single-cell RNA sequencing of heart and skeletal muscle biopsies obtained from living patients with cancers treated with ICTs and admitted to the hospital with myocarditis and/or myositis (overlapping myocarditis plus myositis, n = 10; myocarditis-only, n = 1) or ICT-exposed patients ruled out for toxicity utilized as controls (n = 9). All biopsies were obtained within 96 hours of clinical presentation. Analyses of 58,523 cells revealed CD8+ T cells with a cytotoxic phenotype expressing activation/exhaustion markers in both myocarditis and myositis. Furthermore, the analyses identified a population of myeloid cells expressing tissue-resident signatures and FcγRIIIa (CD16a), which is known to bind IgG and regulate complement activation. Immunohistochemistry of affected cardiac and skeletal muscle tissues revealed protein expression of pan-IgG and complement product C4d, which were associated with the presence of high-titer serum autoantibodies against muscle antigens in a subset of patients. We further identified a population of inflammatory IL1B+TNF+ myeloid cells specifically enriched in myocarditis and associated with greater toxicity severity and poorer clinical outcomes. These results provide insight into the myeloid subsets present in human immune-related myocarditis and myositis tissues and nominate new targets for investigation into rational treatments to overcome these high-mortality toxicities. See related Spotlight by Fankhauser et al., p. 954.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"964-987"},"PeriodicalIF":8.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070610","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}

引用次数: 0

Unveiling Cellular Identities and Gene Expression Pathways in Overlapping Myocarditis and Myositis. 揭示重叠性心肌炎和肌炎的细胞特性和基因表达途径

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-08-01 DOI: 10.1158/2326-6066.CIR-24-0506

Reilly G Fankhauser, Douglas B Johnson, Javid J Moslehi, Justin M Balko

引用次数: 0