Cancer Immunology, Immunotherapy最新文献

{"title":"Periodontitis promotes tumor growth and immune evasion via PD-1/PD-L1.","authors":"Suli Wang, Fujiao Nie, Qiuyue Yin, Haoyang Tian, Pizhang Gong, Jinhong Ju, Jiayi Liu, Pishan Yang, Chengzhe Yang","doi":"10.1007/s00262-024-03865-5","DOIUrl":"10.1007/s00262-024-03865-5","url":null,"abstract":"<p><strong>Background: </strong>Our study investigated the role of experimental periodontitis on tumor growth, local and systemic immunosuppressive status, and programmed death receptor 1 (PD-1) / programmed death ligand 1 (PD-L1) expression in oral squamous cell carcinoma (OSCC) and prostate cancer.</p><p><strong>Methods: </strong>Mouse oral or prostate cancer xenograft models were divided into control, periodontitis and periodontitis + anti-PD-1 groups. Tumor volume and weight were recorded and the levels of relevant immune-suppressive cells and T cells were detected by flow cytometry or immunofluorescence. THP-1 cells were stimulated using conditioned media of LPS-stimulated Cal-27 cells and PD-L1 expression was measured by quantitative real-time PCR, western blotting and immunofluorescence. Tumor specimens from OSCC patients with or without periodontitis were also collected for immunofluorescence.</p><p><strong>Results: </strong>Periodontitis significantly promoted tumor volume and weight. Compared to the control, the proportions of tumor-associated macrophages (TAMs), regulatory T cells (Tregs), PD-L1⁺TAMs and PD-1⁺CD8⁺T cells increased, while CD8⁺T cells decreased in the periodontitis group. Immunofluorescence demonstrated that there was an increase in PD-L1⁺TAMs and PD-1⁺CD8⁺T cells, but a decrease in IFN-γ⁺CD8⁺T cells in both xenografts and clinical OSCC samples with periodontitis. In vitro, LPS-stimulated Cal-27 cells had a stronger potential to induce PD-L1 expression in macrophages compared with unstimulated Cal-27 cells. And the promoting effect of periodontitis on tumor growth and immune evasion was significantly attenuated after anti-PD-1 therapy.</p><p><strong>Conclusion: </strong>Periodontitis may facilitate tumor growth and immune escape evidenced by the increased immune-suppressive cells and the decreased functional T cells, via enhancing PD-1/PD-L1 expression in the tumor microenvironment.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"22"},"PeriodicalIF":4.6,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615425","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":"NLRP12/C1qA positive feedback in tumor-associated macrophages regulates immunosuppression through LILRB4/NF-κB pathway in lung adenocarcinoma.","authors":"Jiaxin Yin, Yuxiao Song, Yang Fu, Jun Wang, Zhimin Zhang, Shasha Ruan, Gaoli Liu, Bicheng Zhang","doi":"10.1007/s00262-024-03880-6","DOIUrl":"10.1007/s00262-024-03880-6","url":null,"abstract":"<p><p>The anti-tumor immune response is greatly hindered by the protumor polarization of tumor-associated macrophages (TAMs). Cancer-related inflammation plays a central role in TAMs protumor polarization. Our study explored the unique positive feedback loop between inflammasome and complement in TAMs. The present study identified NOD-like receptors family pyrin domain containing 12 (NLRP12) formed positive feedback with C1qA and drove TAMs protumor polarization via the LILRB4/NF-κB pathway. In addition, NLRP12 was predominantly expressed in TAMs and was associated with poorer prognosis in lung adenocarcinoma (LUAD) patients. Knocking down LILRB4 inhibited TAMs protumor polarization. NLRP12-overexpressing TAMs promoted tumor cells' malignant progression and inhibited T cells' proliferation and cytotoxic function. Lastly, NLRP12 knockout (NLRP12^-/-) reversed macrophage polarization, enhanced T-cell anti-tumor immunity, and suppressed tumor growth. Our findings highlighted the essential role of NLRP12/C1qA positive feedback loop and the LILRB4/NF-κB pathway in promoting TAMs protumor polarization. Inhibition of NLRP12 suppressed tumor development and promoted immune response. NLRP12 may be a promising target for LUAD immunotherapy.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"16"},"PeriodicalIF":4.6,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615410","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":"Pretransplant immunotherapy increases acute rejection yet improves survival outcome of HCC patients with MVI post-liver transplantation.","authors":"Xinjun Lu, Qi Zhu, Junfeng Cai, Zuozhong Yang, Guangxiang Gu, Li Pang, Mingye Su, Fapeng Zhang, Haoming Lin, Wenrui Wu, Leibo Xu, Chao Liu","doi":"10.1007/s00262-024-03853-9","DOIUrl":"10.1007/s00262-024-03853-9","url":null,"abstract":"<p><p>Immune checkpoint inhibitor (ICI)-based immunotherapy has emerged as the most promising strategy for hepatocellular carcinoma (HCC) downstaging prior to liver transplantation (LT). However, further evidence is required to assess the feasibility and safety of pretransplant ICI exposure. We retrospective analyzed 159 HCC patients who underwent LT at our institution from June 2019 to December 2023, and 39 recipients (39/159, 24.5%) received pretransplant ICI therapy. The perioperative acute rejection rate and rejection-related mortality rate in the ICI group were 23.1% (9/39) and 12.8% (5/39), respectively, which were significantly higher than those in the non-ICI group, at 5% (6/120, P = 0.002) and 0% (0/120, P = 0.001). There was no significant difference in the 90-day post-transplant overall survival (OS) (P = 0.447) and recurrence-free survival (RFS) (P = 0.723) between these two groups. We found 37.1% (59/159) recipients were found to have microvascular invasion (MVI), no matter whether the HCC tumor is within Milan criteria or not. Notably, though MVI was identified as a risk factor for the LT recipients, pretransplant ICI exposure appeared to be a protective factor for HCC patients with MVI which benefits its overall survival. Besides, the RFS and OS in the ICI exposure recipients with MVI were comparable to the non-ICI exposure recipients without MVI. However, no synergistic anti-tumor effects were observed with pretransplant ICI immunotherapy when combined with locoregional of TACE, HAIC, RFA and systematic of lenvatinib or sorafenib downstaging treatments, nor with post-transplant adjuvant of systematic or FOLFOX chemotherapy. Further comprehensive studies are needed to balance the dual natural effects of immunotherapy by optimizing downstaging protocols and patient selection to reduce acute rejection and improve long-term survival.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"18"},"PeriodicalIF":4.6,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615427","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":"Clinical outcomes of chimeric antigen receptor T-cell therapy following autologous hematopoietic stem cell transplantation in 38 patients with refractory/relapsed primary or secondary central nervous system lymphoma.","authors":"Jiaying Wu, Wanying Liu, Yang Cao, Yang Yang, Zhen Shang, Mi Zhou, Yicheng Zhang, Fankai Meng, Xiaojian Zhu, Yi Xiao","doi":"10.1007/s00262-024-03855-7","DOIUrl":"10.1007/s00262-024-03855-7","url":null,"abstract":"<p><strong>Background: </strong>Several reports have indicated that chimeric antigen receptor (CAR) T-cell therapy following autologous hematopoietic stem cell transplantation (ASCT) is a promising strategy for refractory/relapsed (r/r) central nervous system lymphoma (CNSL), but the number of reported cases is limited.</p><p><strong>Methods: </strong>The cohort in this retrospective study consisted of 38 patients with r/r CNSL who received CAR T-cell therapy following ASCT at our center between January 2019 and April 2024. Group comparisons of continuous variables were tested using the unpaired Student's t-test or the Mann-Whitney U-test, while categorical variables were analyzed using Fisher's exact test. The Kaplan-Meier method was employed to estimate survival curves, and group comparisons were performed using the log-rank test.</p><p><strong>Results: </strong>The cohort comprised 38 patients with r/r CNSL, all of whom had active CNS involvement. After therapy, the best overall response rate (ORR) of all patients was 78.9%. Subgroup analysis found that a lower ORR was observed in patients with lactate dehydrogenase levels above the upper limit of normal (60.0% vs. 91.3%, P = 0.039). With a median follow-up of 37.5 months, the estimated 1-year overall survival (OS) and progression-free survival (PFS) rates were 72.8% and 57.4%, respectively. The risk factors associated with PFS was no response to current therapy (adjusted hazard ratio: 22.87, P < 0.001). The incidence rates of severe cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome were both 13.2%. Among the 25 patients with secondary CNSL (SCNSL), the best ORRs were 91.7% for those with CNS lesions only and 61.5% for those with CNS and systemic lesions (P = 0.160), while the estimated 1-year PFS rates were 83.3% and 38.5%, respectively (P = 0.030).</p><p><strong>Conclusions: </strong>CAR T-cell therapy following ASCT shows promising efficacy for r/r CNSL patients. Besides, SCNSL patients with CNS and systemic lesions have inferior treatment efficacy compared to those with CNS lesions only.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"17"},"PeriodicalIF":4.6,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615394","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":"Spontaneous high clonal expansion of Wilms' tumor gene 1-specific cytotoxic T-lymphocytes in patients with Wilms' tumor gene 1-expressing solid tumor.","authors":"Soyoko Morimoto, Yukie Tanaka, Jun Nakata, Fumihiro Fujiki, Kana Hasegawa, Hiroko Nakajima, Sumiyuki Nishida, Akihiro Tsuboi, Naoki Hosen, Naoki Kagawa, Motohiko Maruno, Akira Myoui, Takayuki Enomoto, Shuichi Izumoto, Mitsugu Sekimoto, Naoya Hashimoto, Toshiki Yoshimine, Atsushi Kumanogoh, Yusuke Oji, Yoshihiro Oka, Haruo Sugiyama","doi":"10.1007/s00262-024-03862-8","DOIUrl":"10.1007/s00262-024-03862-8","url":null,"abstract":"<p><p>Wilms' tumor protein 1 (WT1)-targeted immunotherapy has been used in patients with leukemia and solid tumors. However, the spontaneous WT1-specific immune response before WT1 peptide vaccination in patients with WT1-expressing tumors (PTs) remains unclear. Therefore, we investigated whether WT1-specific cytotoxic CD8⁺ T-lymphocytes (CTLs) are clonally expanded in the peripheral blood outside of tumor sites. Clonal expansion of WT1₁₂₆ peptide (a.a.126-134)-specific CTLs (WT1₁₂₆-CTLs) was compared between seven PTs and five healthy volunteers (HVs), and their T-cell receptors (TCRs) were analyzed at the single-cell level. Overall, 433 and 351 TCR β-chains of WT1₁₂₆-CTLs were detected from PTs and HVs, respectively, and complementarity-determining region 3 was sequenced for clonality analysis. The frequencies of WT1₁₂₆-CTLs were higher in human leukocyte antigen (HLA)-A*02:01⁺ PTs than in HLA-A*02:01⁺ HVs, although the difference was not statistically significant. WT1₁₂₆-CTLs of differentiated types, including memory and effector, were higher in PTs than in HVs; whereas, those of the naïve type were higher in HVs than in PTs. WT1₁₂₆-CTL clonality was significantly higher in PTs than in HVs. Furthermore, the frequency of effector WT1₁₂₆-CTLs positively correlated with WT1₁₂₆-CTL clonality in PTs; whereas, the frequency of naïve phenotype WT1₁₂₆-CTLs tended to be negatively correlated with clonality. In conclusion, these results suggest that the WT1 protein in tumor cells is highly immunogenic, thereby stimulating endogenous naïve-type WT1₁₂₆-CTLs and enabling them to clonally expand and differentiate into effector-type WT1₁₂₆-CTLs.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"15"},"PeriodicalIF":4.6,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11543974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603389","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":"Differences in immune-related toxicity between PD-1 and PD-L1 inhibitors: a retrospective cohort study in patients with advanced cancer.","authors":"Cecilia Olsson Ladjevardi, Marcus Skribek, Anthoula Koliadi, Viktoria Rydén, Ali Inan El-Naggar, Evangelos Digkas, Antonios Valachis, Gustav J Ullenhag","doi":"10.1007/s00262-024-03869-1","DOIUrl":"10.1007/s00262-024-03869-1","url":null,"abstract":"<p><p>Immunotherapy with PD-1 or PD-L1 inhibitors has become an essential treatment strategy for a growing number of malignancies. These treatments have a risk for immune-related adverse events (IRAEs). Pooled analyses based on clinical trials show a favorable toxicity profile for treatment with PD-L1 compared to PD-1 inhibitors. This study aimed to investigate differences in IRAEs between patients with advanced solid malignances treated with PD-L1 and PD-1 inhibitors in a real-world setting. We conducted a retrospective cohort study at four Swedish Regions. Patients (n = 605) treated for advanced cancer with a PD-L1 or PD-1 inhibitor in monotherapy between June 2016 and August 2022 were included. Non-small cell lung cancer (NSCLC) was the most common malignant disease (n = 251; 41.5%), followed by malignant melanoma (n = 173; 28.6%), renal cell carcinoma (n = 71; 11.7%) and urothelial carcinoma (n = 35; 5.8%). Among patients receiving PD-L1 inhibitors, NSCLC (94.4%) was the predominant malignancy, whereas for those treated with PD-1 inhibitor, malignant melanoma constituted the most prevalent malignancy (34.5%). Discontinuation of treatment due to IRAEs overall and IRAEs grade ≥ 2 were significantly less common in patients treated with PD-L1 compared to PD-1 inhibitors [Odds Ratio (OR): 0.38 (95% Confidence Interval (CI) 0.16-0.88) and OR: 0.63 (95% CI 0.35-0.98) respectively]. Any grade IRAE, IRAE grade ≥ 3 and multiple IRAEs were numerically more frequent in patients treated with PD-1 inhibitors.In conclusion, our study of patients with advanced solid malignancies in a real-world setting supports the results from clinical trials demonstrating a favorable toxicity profile for PD-L1 inhibitors versus PD-1 inhibitors.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"14"},"PeriodicalIF":4.6,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11543953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603293","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":"Efficacy, safety, and biomarker analysis of TACE combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma: a real-world study.","authors":"Lingzhan Meng, Hu Li, Yingjie Ji, Peng Yu, Zizheng Wang, Li Cao, Bin Shi, Yanling Shao, Jin Yan, Yinjie Gao, Zhenyu Zhu","doi":"10.1007/s00262-024-03857-5","DOIUrl":"10.1007/s00262-024-03857-5","url":null,"abstract":"<p><strong>Background: </strong>The integration of transarterial chemoembolization (TACE) with systemic therapy has demonstrated improved survival outcomes in patients with unresectable hepatocellular carcinoma (HCC). However, there is limited evidence evaluating the combination of TACE with the systemic regimen of anti-PD-1/L1 inhibitor plus lenvatinib. This study aims to assess the efficacy and safety of TACE combined with lenvatinib and sintilimab in unresectable HCC patients.</p><p><strong>Methods: </strong>Unresectable HCC patients who received TACE in combination with sintilimab plus Lenvatinib as first-line treatment from 1 January 2020 to 31 March 2023 were included for the analysis. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were evaluated by modified Response Evaluation Criteria in Solid Tumors criteria. Exploratory biomarker analysis was conducted.</p><p><strong>Results: </strong>The study included 70 patients with unresectable HCC, predominantly male and infected with Hepatitis B. The median follow-up duration for the whole cohort was 13.8 months (95% CI 11.08-16.7). The ORR was 61.4% (95% CI, 49.0%-72.8%) and the DCR was 68.6% (95%CI, 56.4%-79.2%). The median PFS was 13.2 months (95% CI 11.0-NA), with a corresponding 1-year PFS rate of 50.3% (95% CI 39.7%-65.5%). The median OS was not reached, and the 1-year OS rate was 89.3% (95% CI 81.4%-97.9%). The most common treatment-related adverse events (TRAEs) were fatigue 38.6% (27/70), hypertension 32.9% (23/70), and hand-foot syndrome 31.4% (22/70). Most TRAEs were mild-to-moderate and manageable. In addition, significant predictive value was found in alpha-fetoprotein levels (AFP), with patients showing a level of decrease post-treatment having better PFS.</p><p><strong>Conclusion: </strong>The combination regimen demonstrated promising efficacy in treating unresectable HCC, accompanied by manageable safety profiles. Furthermore, the results of this investigation suggest that AFP holds promise as predictive biomarkers for this treatment strategy.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"13"},"PeriodicalIF":4.6,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582038","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":"Dendritic cell maturation is induced by p53-armed oncolytic adenovirus via tumor-derived exosomes enhancing systemic antitumor immunity.","authors":"Tomoko Ohtani, Shinji Kuroda, Nobuhiko Kanaya, Yoshihiko Kakiuchi, Kento Kumon, Masashi Hashimoto, Chiaki Yagi, Ryoma Sugimoto, Satoru Kikuchi, Shunsuke Kagawa, Hiroshi Tazawa, Yasuo Urata, Toshiyoshi Fujiwara","doi":"10.1007/s00262-024-03849-5","DOIUrl":"10.1007/s00262-024-03849-5","url":null,"abstract":"<p><p>Dendritic cells (DCs) are crucial in cancer immunity, because they activate cytotoxic T cells by presenting tumor antigens. Recently, oncolytic virus therapy has been recognized as a systemic immune stimulator. We previously developed a telomerase-specific oncolytic adenovirus (OBP-301) and a p53-armed OBP-301 (OBP-702), demonstrating that these viruses strongly activate systemic antitumor immunity. However, their effects on DCs remained unclear. In the present study, the aim was to elucidate the mechanisms of DC activation by OBP-702, focusing particularly on tumor-derived exosomes. Exosomes (Exo53, Exo301, or Exo702) were isolated from conditioned media of human or murine pancreatic cancer cell lines (Panc-1, MiaPaCa-2, and PAN02) after treatment with Ad-p53, OBP-301, or OBP-702. Exo702 derived from Panc-1 and MiaPaCa-2 cells significantly upregulated CD86, CD80, CD83 (markers of DC maturation), and IFN-γ in DCs in vitro. Similarly, Exo702 derived from PAN02 cells upregulated CD86 and IFN-γ in bone marrow-derived DCs in a bilateral PAN02 subcutaneous tumor model. This DC maturation was inhibited by GW4869, an inhibitor of exosome release, and anti-CD63, an antibody targeting the exosome marker. Intratumoral injection of OBP-702 into PAN02 subcutaneous tumors significantly increased the presence of mature DCs and CD8-positive T cells in draining lymph nodes, leading to long-lasting antitumor effects through the durable activation of systemic antitumor immunity. In conclusion, tumor-derived exosomes play a significant role in DC maturation following OBP-702 treatment and are critical for the systemic activation of antitumor immunity, leading to the abscopal effect.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"12"},"PeriodicalIF":4.6,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582082","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":"Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer.","authors":"Jenny Ling-Yu Chen, Chun-Kai Pan, Li-Cheng Lin, Yu-Sen Huang, Tsung-Hsuan Huang, Shu-Jyuan Yang, Sung-Hsin Kuo, Yu-Li Lin","doi":"10.1007/s00262-024-03864-6","DOIUrl":"10.1007/s00262-024-03864-6","url":null,"abstract":"<p><p>We investigated the combined effects of ataxia telangiectasia and Rad3-related (ATR) inhibition, ablative radiotherapy, and immune checkpoint inhibitor (ICI) therapy against lung cancer. ATR inhibitor was administered combined with ablative radiotherapy to assess its radiosensitizing effect on lung cancer cells. Treatment response and survival were evaluated in vivo using A549 xenograft flank tumor and synchronous LLC lung and flank tumor mouse models. Mice received ablative radiotherapy (12 Gy/d for 2 d), ATR inhibitor, and ICI. The tumor microenvironment was assessed in irradiated flank and non-irradiated lung tumors. Programmed death-ligand 1 expression was upregulated after irradiation. ATR inhibition attenuated this upregulation. ATR inhibitor pretreatment decreased cell survival after irradiation by inhibiting DNA double-strand break repair, inducing mitotic cell death, and altering cell cycle progression. ATR inhibition enhanced radiation-induced damage-associated molecular patterns determined by high mobility group box 1 quantification and activated the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Combined ATR inhibition and ablative radiotherapy inhibited tumor growth and improved survival in mice. Adding ICI therapy further enhanced local antitumor effects, reducing the metastatic lung tumor burden and remodeling the tumor microenvironment through immunogenic cell death induction and enhanced immune cell infiltration. Triple therapy increased immune cell infiltration in distant non-irradiated lung tumors and stimulated the generation of protective T-cell immunity in splenocytes. Safety analysis showed minimal toxicity. ATR inhibition enhanced the efficacy of ablative radiotherapy and immunotherapy in lung cancer. These findings underscore the importance of combination therapies for enhancing systemic antitumor immune responses and outcomes.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"8"},"PeriodicalIF":4.6,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564102","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":"Differential T cell accumulation within intracranial and subcutaneous melanomas is associated with differences in intratumoral myeloid cells.","authors":"Katarzyna Stasiak, Aaron D Stevens, Ashley C Bolte, Colleen T Curley, Mirna Perusina Lanfranca, Robin S Lindsay, Ukpong B Eyo, John R Lukens, Richard J Price, Timothy N J Bullock, Victor H Engelhard","doi":"10.1007/s00262-024-03832-0","DOIUrl":"10.1007/s00262-024-03832-0","url":null,"abstract":"<p><p>Patients with metastatic brain melanomas (MBM) experience shorter-lasting survival than patients with extracranial metastases, and this is associated with a higher fraction of dysfunctional CD8 T cells. The goal of this study was to understand the underlying cause of T cell dysfunction in MBM. To accomplish this, we compared murine B16 melanomas implanted intracranially (IC) or subcutaneously (SC). CD8 T cell activation was not altered, but representation in IC tumors was lower. Transferred activated or naïve CD8 T cells accumulated in similar numbers in both tumors, suggesting that the vasculature does not differentially impair T cell presence. Surprisingly, we found no evidence for T cell activation in draining lymph nodes of SC or IC tumor-bearing mice, consistent with the fact that dendritic cells (DC) that had acquired tumor antigen showed an immature phenotype. Instead, T cell activation occurred within both tumors, where the majority of tumor antigen⁺ myeloid cells were found. While, the numbers of intratumoral DC were comparable, those in IC tumors acquired less tumor antigen, and were alternatively matured based on upregulation of MHCII without upregulation of CD86. Additionally, in IC tumors, the largest population of tumor antigen⁺ myeloid cells were microglia. However, their presence did not influence either antigen acquisition or the phenotype of other myeloid cell populations. Overall, our data suggest that diminished representation of CD8 T cells in IC tumors is a consequence of alternatively matured DC and/or microglia that induce distinctly activated T cells, which ultimately fail to continue to accumulate inside the tumor.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"10"},"PeriodicalIF":4.6,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564104","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}