Cancer Immunology, Immunotherapy最新文献

{"title":"Q11, a CYP2E1 inhibitor, exerts anti-hepatocellular carcinoma effect by inhibiting M2 macrophage polarization.","authors":"Cunzhen Zhang, Yan Fang, Mengxue Guo, Liming Tang, Yurong Xing, Jun Zhou, Yuanyuan Guo, Yuhan Gu, Qiang Wen, Na Gao, Haiwei Xu, Hailing Qiao","doi":"10.1007/s00262-024-03912-1","DOIUrl":"10.1007/s00262-024-03912-1","url":null,"abstract":"<p><p>Despite significant advancements in cancer immunotherapy, many patients continue to respond poorly. Novel therapeutic strategies and drugs are urgently needed. Here, we found that CYP2E1 is upregulated in M2 macrophages. The CYP2E1 inhibitor, Q11, could inhibit M2 macrophage polarization, while CYP2E1 overexpression could promote it. Increased levels of CYP2E1 and M2 macrophages in the tumor microenvironment of HCC patients correlate with poor prognosis. Q11 could inhibit tumor cells by targeting M2 macrophages rather than directly attacking tumor cells. Both Q11 and Cyp2e1 knockout could effectively suppress tumor growth. Q11 reduces the production of CYP2E1 metabolites ( ±)9(10)-DiHOME and ( ±)12(13)-DiHOME, thus attenuating PPARγ activation and M2 macrophage polarization. In summary, our findings suggest that Q11 could suppress M2 macrophage polarization by modulating the CYP2E1/( ±)9(10)-DiHOME or ( ±)12(13)-DiHOME/PPARγ axis, indicating that CYP2E1 may be a potential therapeutic target for HCC, and its inhibitor Q11 may be a potential drug for the treatment of HCC.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"35"},"PeriodicalIF":4.6,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11685367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909484","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":"Targeting OAS3 for reversing M2d infiltration and restoring anti-tumor immunity in pancreatic cancer.","authors":"Shaopeng Zhang, Ximo Xu, Kundong Zhang, Changzheng Lei, Yitian Xu, Pengshan Zhang, Yuan Zhang, Haitao Gu, Chen Huang, Zhengjun Qiu","doi":"10.1007/s00262-024-03898-w","DOIUrl":"10.1007/s00262-024-03898-w","url":null,"abstract":"<p><p>Abundant infiltration of tumor-associated macrophages (TAMs) within the tumor stroma plays a pivotal role in inducing immune escape in pancreatic cancer (PC). Lactate serves as a direct regulator of macrophage polarization and functions, although the precise regulation mechanism remains inadequately understood. Our study revealed that PC cells (PCs) promote macrophage polarization toward M2d through high lactate secretion. M2d is characterized by elevated secretion of IL-10 and VEGF-A, which diminish CD8⁺T cells cytotoxicity and promote tumor neoangiogenesis simultaneously. Additionally, we identify 2,5'-oligoadenylate synthase 3 (OAS3) as an essential regulator of M2d polarization, upregulated by PCs via lactate/METTL3/OAS3 axis. Increased OAS3 expression in TAMs correlates with m6A modification mediated by METTL3 on OAS3 mRNA and is associated with poorer prognosis in PC patients. OAS3 deficiency in macrophages substantially impairs IL-10^highVEGF-A^highM2d polarization and their pro-tumor functions while enhancing the therapeutic efficacy of gemcitabine and anti-PD-L1 mAb in humanized mouse models. In conclusion, OAS3 presents as a promising immune therapeutic target for reversing IL-10^highVEGF-A^highM2d infiltration and restoring CD8⁺T cell-mediated anti-tumor immunity in pancreatic cancer.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"37"},"PeriodicalIF":4.6,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11685377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909485","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":"Integration of bulk and single-cell RNA-seq reveals prognostic gene signatures in patients with bladder cancer treated with immune checkpoint inhibitors.","authors":"Mina Cho, Hyun Chang, Ju Han Kim","doi":"10.1007/s00262-024-03839-7","DOIUrl":"10.1007/s00262-024-03839-7","url":null,"abstract":"<p><p>Immune checkpoint inhibitors have significantly advanced research in oncology and are used to successfully treat patients with bladder cancer (BC). However, as the benefits of programmed death-1/ programmed death-ligand-1 blockade immunotherapy do not extend to all patients with BC, biomarkers are required to improve prognostic stratification. This study aims to identify reliable biomarkers to enhance the prediction of treatment outcomes. Bulk RNA expression data from a BC cohort (GSE176307) receiving ICI and single-cell sequencing data from patients with BC (GSE135337) were collected. We identified differentially expressed genes (DEGs) within cells that were associated with favorable survival outcomes and developed a predictive bladder cancer gene signature (BC-GS). Subsequently, we performed pathway enrichment analysis using the Reactome database. We used two independent datasets to validate the BC-GS. Patients with low BC-GS had a significantly shorter overall survival (OS) than those with high BC-GS (p < 0.05, p < 0.001, respectively). Additionally, patients with a concurrently low BC-GS score and low tumor mutation burden (TMB) in GSE176307 and the two validation datasets exhibited an increased risk of death. Genes in the BC-GS were predominantly involved in CD8⁺ T cell activation, antigen presentation, and immune checkpoint pathways. CIBERSORT analysis revealed differences in CD4⁺ T cells and macrophages between the high and low BC-GS groups. This study demonstrated the prognostic significance of the BC-GS in patients with BC treated with ICI. The combined assessment of the BC-GS and TMB may provide a sophisticated prognostic approach to enhance patient stratification for ICI treatment in BC.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"28"},"PeriodicalIF":4.6,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871582","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":"Artificial neural network systems to predict the response to sintilimab in squamous-cell non-small-cell lung cancer based on data of ORIENT-3 study.","authors":"Tongji Xie, Guangyu Fan, Le Tang, Puyuan Xing, Yuankai Shi","doi":"10.1007/s00262-024-03886-0","DOIUrl":"10.1007/s00262-024-03886-0","url":null,"abstract":"<p><strong>Background: </strong>Existing biomarkers and models for predicting response to programmed cell death protein 1 monoclonal antibody in advanced squamous-cell non-small cell lung cancer (sqNSCLC) did not have enough accuracy. We used data from the ORIENT-3 study to construct artificial neural network (ANN) systems to predict the response to sintilimab for sqNSCLC.</p><p><strong>Methods: </strong>Four ANN systems based on bulk RNA data to predict disease control (DC), immune DC (iDC), objective response (OR) and immune OR (iOR) were constructed and tested for patients with sqNSCLC treated with sintilimab. The mechanism exploration on the bulk and the spatial level were performed in patients from the ORIENT-3 study and the real world, respectively.</p><p><strong>Findings: </strong>sqNSCLC patients with different responses to sintilimab showed each unique transcriptomic spectrum. Four ANN systems showed high accuracy in the test cohort (AUC of DC, iDC, OR and iOR were 0.83, 0.89, 0.93 and 0.94, respectively). The performance of ANN systems was better than that of linear model systems and showed high stability. The mechanism exploration on the bulk level suggested that patients with lower ANN system scores (worse response) had a higher ratio of immune-related pathways enrichment. The mechanism exploration on the spatial level indicated that patients with better response to immunotherapy had fewer clusters of both tumor and cytotoxicity T cell spots.</p><p><strong>Interpretation: </strong>The four ANN systems showed high accuracy, robustness and stability in predicting the response to sintilimab for patients with sqNSCLC.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"29"},"PeriodicalIF":4.6,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871579","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":"Target trial emulation to evaluate the effect of immune-related adverse events on outcomes in metastatic urothelial cancer.","authors":"Renate Pichler, Josef Fritz, Sarah Maier, Melanie R Hassler, Johanna Krauter, David D Andrea, Ekaterina Laukhtina, Kilian Gust, Keiichiro Mori, Karl H Tully, Dora Niedersuess-Beke, Lea Korber, Jasmin Alija Spiegelberg, Thomas Bauernhofer, José D Subiela, Roman Mayr, Andreas Kronbichler, Marco Moschini, Jeremy Teoh, Benjamin Pradere, Shahrokh F Shariat, Hanno Ulmer, Laura S Mertens","doi":"10.1007/s00262-024-03871-7","DOIUrl":"10.1007/s00262-024-03871-7","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) are an important therapeutic pillar in metastatic urothelial carcinoma (mUC). The occurrence of immune-related adverse events (irAEs) appears to be associated with improved outcomes in observational studies. However, these associations are likely affected by immortal time bias and do not represent causal effects. The aim of this study was to assess the effect of irAEs on outcomes while correcting for immortal time bias, using target trial emulation (TTE).</p><p><strong>Methods: </strong>TTE was contrasted to adjusted naïve and time-updated Cox models. We performed a multi-institutional retrospective study involving mUC patients under ICI. The primary objective was to assess the impact of irAEs on progression-free survival (PFS) and overall survival (OS). Secondary endpoints included the influence of irAEs on objective response rates (ORRs) to ICI and the influence of systemic corticosteroids on outcomes.</p><p><strong>Results: </strong>Among 335 patients (median age: 69 yrs), 69.6% received ICI in the second line or further lines. During a median follow-up of 21.1 months, 122 (36.4%) patients developed irAEs of any grade (grade ≥ 3: 14.9%). Hazard ratios (HRs) for PFS ranged from 0.37 for naïve adjusted Cox model to 0.88 (95% confidence interval (CI), 0.59-1.30) with time-updated covariates, and from 0.41 to 1.10 (95% CI, 0.69-1.75) for OS. TTE accounting for immortal time bias yielded a HR of 1.02 (95% CI, 0.72-1.44) for PFS, and 0.90 (95% CI, 0.62-1.30) for OS. In contrast to the naïve Cox model (HR = 2.26, 95% CI 1.26-4.05), the presence of irAEs was no longer a predictive factor for improved ORR in time-updated Cox models (HR = 1.27, 95% CI 0.68-2.36) and TTE (HR = 1.43, 95% CI 0.89-2.29). In patients with irAEs, systemic corticosteroids did not negatively impact survival.</p><p><strong>Conclusion: </strong>Using TTE, we were able to show that the occurrence of irAEs is no longer associated with better survival or improved response rates to ICI in mUC patients, in contrast to the naïve analysis. These findings demonstrate that TTE is a suitable formal framework to avoid immortal time bias in studies with time-dependent non-interventional exposures.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"30"},"PeriodicalIF":4.6,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871583","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":"HLA-G high-expressor 3'UTR markers are linked to gastric cancer development and survival.","authors":"Christian Vaquero-Yuste, Ignacio Juarez, Marta Molina-Alejandre, Elisa María Molanes-López, Alberto Gutiérrez-Calvo, Adela López-García, Inmaculada Lasa, Remedios Gómez, Antonio Arnaiz-Villena, Jose Manuel Martín-Villa","doi":"10.1007/s00262-024-03771-w","DOIUrl":"10.1007/s00262-024-03771-w","url":null,"abstract":"<p><p>Gastric cancer ranks fifth in both world prevalence and lethality, with a 5-year survival of less than 30%. HLA-G, a non-classical class I HLA gene, has emerged as a potential marker for cancer susceptibility and prognosis due to its immunomodulatory properties. Its level of expression is regulated by polymorphisms in the 3' untranslated region (3'UTR) polymorphisms, which form various combined haplotypes (UTR-1 to -9). In this study, we examined HLA-G 3'UTR polymorphisms in paired tissue samples from 111 patients with gastric adenocarcinoma and 119 healthy controls. Polymorphism analysis was performed using PCR and Sanger sequencing, followed by statistical analysis using SNPStats software. Survival analysis was conducted using Kaplan-Meier curves and multivariate Cox regression models. High-expressor HLA-G 3'UTR haplotypes (UTR-1 and UTR-6) were significantly associated with gastric cancer susceptibility, indicating a potential role in tumor immune evasion. Additionally, the 14 base pair insertion/deletion polymorphism (14 bp I/D) emerged as a prognostic marker, with D/D genotype carriers showing lower survival rates compared to I/D and I/I genotype carriers. Our study highlights the clinical relevance of HLA-G polymorphisms in gastric cancer, suggesting their potential as prognostic markers and therapeutic targets. Further elucidation of HLA-G-related pathways could lead to personalized treatment strategies and improved patient outcomes in gastric cancer.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"26"},"PeriodicalIF":4.6,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11569108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643477","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":"Hepatitis associated with immune checkpoint inhibitors-based combinations of other therapies: A real-world pharmacovigilance analysis based on the FDA adverse event reporting system (FAERS) database.","authors":"Zhaohui Li, Zixiang Zhou, Nan Zhang, Binhe Tian, Xiangqi Chen, Haitao Zhao, Hanping Wang","doi":"10.1007/s00262-024-03858-4","DOIUrl":"10.1007/s00262-024-03858-4","url":null,"abstract":"<p><strong>Background: </strong>The combination regimen with immune checkpoint inhibitors (ICIs) and other therapies has been widely applied for patients with non-small-cell lung cancer (NSCLC). To date, no literature has systematically addressed the risk of hepatitis associated with the combination therapy. We conducted this pharmacovigilance analysis using the Food and Drug Administration Adverse Event Reporting System (FAERS).</p><p><strong>Patients and methods: </strong>A total of 587,016 NSCLC reports were extracted from FAERS database spanning from the first quarter of 2013 to the second quarter of 2023. After filtering duplicate reports, logistic regression model was used to detect safety signals, and multivariable logistic regression model was used to confirm the interaction between ICI and other drugs.</p><p><strong>Results: </strong>Of the 81,512 patients with NSCLC, 2785 cases developed hepatitis. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with targeted therapy (TT) was the highest 1.64 (95% CI, 1.32-2.02; P < 0.0001) among all therapies, while that of TT and ICI treatment were 1.07 (95% CI, 0.98-1.17; P = 0.1097) and 1.12 (95% CI, 1.03-1.22; P = 0.0111), respectively. The adjusted ROR for the interaction effect was 1.64 (95% CI, 1.32-2.02; P < 0.0001). Furthermore, the adjusted ROR of ICI combined with KRAS-targeted drugs was the highest 3.03 (95% CI, 1.49-5.93; P = 0.0016) among all targeted drugs, with an adjusted ROR of 3.03 (95% CI, 1.49-5.93; P = 0.0016), indicating a meaningful interaction of these two kinds of drugs.</p><p><strong>Conclusion: </strong>We confirmed that combination treatment of ICI and TT is associated with the amplified risk of hepatitis, which is partly due to the interaction between ICI and TT, and the KRAS-targeted drugs may harbor the highest potential for hepatitis induction among TT drugs when combined with ICI. Besides, the combination treatment of ICI- and KRAS-targeted drugs also increases the incidence of colitis, pulmonary embolism and dehydration.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"25"},"PeriodicalIF":4.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638452","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":"Hepatic arterial infusion chemotherapy combined with systemic therapy sequentially or simultaneously for advanced hepatocellular carcinoma.","authors":"Yu-Zhe Cao, Jia-Yu Pan, Guang-Lei Zheng, Chao An, Meng-Xuan Zuo","doi":"10.1007/s00262-024-03872-6","DOIUrl":"10.1007/s00262-024-03872-6","url":null,"abstract":"<p><strong>Background and aims: </strong>The goal of this study was to compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with targeted therapy and PD-(L)1 blockade (triple therapy), either sequentially (SE) or simultaneously (SI), in the treatment of Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC).</p><p><strong>Approach and results: </strong>From January 1, 2018, to June 1, 2022, 575 patients with BCLC stage C HCC who underwent SE or SI triple therapy were retrospectively enrolled. Propensity score matching (PSM; 1:1) was performed to eliminate possible confounder imbalances across cohorts. We used the Kaplan-Meier method and a log-rank test to compare the overall survival (OS) and progression-free survival (PFS) rates between the SI and SE groups. The tumor response and the incidence of adverse events (AEs) were reported. After PSM, 182 patients in each of the two groups were matched. The median OS in the SI group was significantly longer than that in the SE group (28.8 vs. 16.1 months; P = 0.002), and the median PFS was significantly improved in the SI versus SE group (9.6 vs. 7.0 months; P = 0.01). The objective response rate based on the mRECIST was higher in the SI group (58% vs. 37%; P < 0.001). The total incidences of grade 3-4 AEs were 111/182 (60.9%) and 128/182 (70.3%) in the SE and SI groups, respectively. No grade 5 AEs were reported in either group.</p><p><strong>Conclusions: </strong>Simultaneous HAIC plus targeted therapy and PD-(L)1 blockade significantly improved outcomes compared to the sequential regimen in patients with BCLC stage C HCC, with no unexpected AEs.</p><p><strong>Clinical relevance statement: </strong>The patients who received hepatic arterial infusion chemotherapy combined with targeted therapy and PD-(L)1 blockade simultaneously have a better prognosis than those who received it sequentially.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"24"},"PeriodicalIF":4.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615399","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":"Loop33 × 123 CAR-T targeting CD33 and CD123 against immune escape in acute myeloid leukemia.","authors":"Haotian Ma, Zhifeng Yan, Runxia Gu, Yingxi Xu, Shaowei Qiu, Haiyan Xing, Kejing Tang, Zheng Tian, Qing Rao, Min Wang, Jianxiang Wang","doi":"10.1007/s00262-024-03847-7","DOIUrl":"10.1007/s00262-024-03847-7","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapy, such as chimeric antigen receptor T (CAR-T) cells targeting CD33 or CD123, has been well developed over the past decade for the treatment of acute myeloid leukemia (AML). However, the inability to sustain tumor-free survival and the possibility of relapse due to antigen loss have raised concerns. A dual targeting of CD33 and CD123 is needed for better outcomes.</p><p><strong>Methods: </strong>Based on our previously constructed CD33 and CD123 monovalent CAR-T, Loop33 × 123 and Loop123 × 33 CAR-T were constructed with molecular cloning techniques. All CAR-T cells were generated by lentivirus transduction of T cells from healthy donors. Phenotype detection was evaluated on day 7 concerning activation, exhaustion, and subtype proportions. Coculture killing assays were conducted using various AML cell lines and primary AML cells. Degranulation and cytokine secretion levels were detected by flow cytometry. Cell-derived xenograft models were established using wild-type Molm 13 cell lines, or a mixture of Molm 13-KO33 and Molm 13-KO123 cells as an ideal model of immune escape. By monitoring body weight and survival of tumor-bearing mice, Loop33 × 123 and Loop123 × 33 CAR-T cells were further assessed for their efficacy in vivo.</p><p><strong>Results: </strong>In vitro study, our results demonstrated that Loop33 × 123 CAR-T cells could efficiently eliminate AML cell lines and primary AML cells with elevated degranulation and cytokine secretion levels. Compared with our previously constructed monovalent CD33 or CD123 CAR-T cells, Loop33 × 123 CAR-T cells showed superior advantages in an immune escape model. In vivo studies further confirmed that Loop33 × 123 CAR-T cells could effectively prolong the survival of mice without significant toxicity. However, Loop123 × 33 CAR-T cells failed to show the same effects. Furthermore, Loop33 × 123 CAR-T cells efficiently circumvented potential immune escape, a challenge where monovalent CAR-T cells failed.</p><p><strong>Conclusions: </strong>Loop33 × 123 CAR-T targeting CD33 and CD123 could efficiently eliminate AML cells and prolong survival of tumor-bearing mice, while addressing the issue of immune escape.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"20"},"PeriodicalIF":4.6,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615406","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":"Overcoming immunosuppression in cancer: how ketogenic diets boost immune checkpoint blockade.","authors":"Victoria E Stefan, Daniela D Weber, Roland Lang, Barbara Kofler","doi":"10.1007/s00262-024-03867-3","DOIUrl":"10.1007/s00262-024-03867-3","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) is now part of the standard of care in the treatment of many forms of cancer, yet it lacks efficacy in some patients, necessitating adjunct therapies to support the anti-tumor immune response. Ketogenic diets (KDs), i.e., high-fat low-carbohydrate diets, have been shown to have antiproliferative and immunomodulatory effects in various preclinical cancer studies. Here, we review current knowledge of the complex interplay of KDs and the anti-tumor immune response in the context of ICB therapy, to update our understanding of diet-induced immunometabolic reprogramming in cancer. Preclinical cancer studies have revealed increased activation of and infiltration by tumor-fighting immune cells, especially CD8+ T cells, but also M1 macrophages and natural killer cells, in response to a KD regimen. In contrast, immune-suppressive cells such as regulatory CD4+ T lymphocytes, M2 macrophages, and myeloid-derived suppressor cells were reported to be decreased or largely unaffected in tumors of KD-fed mice. KDs also showed synergism with ICB therapy in several preclinical tumor studies. The observed effects are ascribed to the ability of KDs to improve immune cell infiltration and induce downregulation of immune-inhibitory processes, thus creating a more immunogenic tumor microenvironment. The studies reviewed herein show that altering the metabolic composition of the tumor microenvironment by a KD can boost the anti-tumor immune response and diminish even immunotherapy-resistant as well as immunologically \"cold\" tumors. However, the exact underlying mechanisms remain to be elucidated, requiring further studies before KDs can be successfully implemented as an adjunct tumor therapy to improve survival rates for cancer patients.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"23"},"PeriodicalIF":4.6,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615413","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}