Cancer immunology, immunotherapy : CII最新文献

{"title":"Clinical, immune cell, and genetic features predicting survival and long-term response to first-line chemo-immunotherapy treatment for non-small cell lung cancer.","authors":"Liling Huang, Haohua Zhu, Liyuan Dai, Yu Feng, Xinrui Chen, Zucheng Xie, Xingsheng Hu, Yutao Liu, Xuezhi Hao, Lin Lin, Hongyu Wang, Shengyu Zhou, Jiarui Yao, Le Tang, Xiaohong Han, Yuankai Shi","doi":"10.1007/s00262-025-04022-2","DOIUrl":"10.1007/s00262-025-04022-2","url":null,"abstract":"<p><strong>Introduction: </strong>Chemo-immunotherapy has become a standard of care for the first-line treatment of non-small cell lung cancer (NSCLC), but currently still lacks reliable markers to predict therapeutic efficacy and long-term response (LTR).</p><p><strong>Methods: </strong>In this study, we retrospectively summarized the survival outcome of 319 patients with locally advanced or metastatic NSCLC who received anti-programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) based therapy from January 1st, 2018 to February 28th, 2022 at the Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College. Then a comprehensive analysis of the association of LTR or survival outcomes with various characteristics including clinical parameters, peripheral blood lymphocyte subsets and common gene mutations in 167 NSCLC patients who received first-line anti-PD-1 plus chemotherapy treatment was conducted. LTR was defined as progression-free survival (PFS) exceeding 24 months, while non-responders had a PFS of less than 6 months.</p><p><strong>Results: </strong>With a median follow-up time of 32.1 months (95% confidence interval [CI] 29.2-38.0), the median overall survival (OS) was 29.9 months (95% CI 23.6-37.5) in locally advanced or metastatic NSCLC receiving anti-PD-1/PD-L1 based treatment. Among 167 patients who received the first-line chemo-immunotherapy, 25.1% (n = 42) achieved LTR. Independent baseline predictors of LTR included age < 65 years (odds ratio [OR] = 3.22, p = 0.024), overweight or obesity (body mass index [BMI] ≥ 24 kg/m², OR = 3.26, p = 0.020), and a C-reactive protein/albumin ratio (CAR) score < 0.07 (OR = 9.94, p = 0.039). In multivariate cox analysis, both patients with higher CAR scores of ≥ 0.07 (hazard ratio [HR] = 2.83, p = 0.016) and those who were underweight (BMI < 18.5 kg/m²) (HR = 4.52, p = 0.005) were observed with significantly shorter OS. A peripheral B cell percentage ≥ 14.5% was more prevalent among LTR patients (OR = 9.23, p = 0.045) after adjusting for age, BMI and TNM stage. Additionally, the presence of TP53 mutation (16/66) was associated with non-response to first-line chemo-immunotherapy (p = 0.048) and shorter PFS (p = 0.028) and OS (p = 0.023) outcomes in univariate analysis.</p><p><strong>Conclusions: </strong>This study provides some new insights into the features and predictors significantly associated with LTR and survival in NSCLC patient receiving first-line treatment of anti-PD-1 plus chemotherapy. Those whose age < 65 years, overweight or obesity, or has a baseline CAR score < 0.07 are more likely to achieve optimal benefit from the first-line treatment of chemo-immunotherapy.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 7","pages":"219"},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LAG3 as a marker of immune activation in esophageal squamous carcinoma treated with concurrent chemoradiotherapy.","authors":"Yuxuan Zhang, Zijing Zhou, Yuanyuan Rui, Fanhao Kong, Zhoubo Guo, Gang Zhao, Jun Wang, Jiacheng Li, Fangdong Zhao, Hui Huang, Fang Fang, Jiarui Zhang, Tian Zhang, Wencheng Zhang, Ping Wang, Xi Chen, Peng Zhen, Qingsong Pang","doi":"10.1007/s00262-025-04076-2","DOIUrl":"10.1007/s00262-025-04076-2","url":null,"abstract":"<p><strong>Introduction: </strong>Esophageal squamous carcinoma (ESCC) is a common malignant tumor of the gastrointestinal tract with high morbidity and mortality rates. Lymphocyte activation gene-3 (LAG3), an important suppressive immune checkpoint in tumor immunity, exhibits a wobbling effect in the prediction of ESCC efficacy.</p><p><strong>Methods: </strong>Tumor bite paraffin-embedded specimens from 84 patients diagnosed with ESCC, all of whom received radical concurrent chemoradiotherapy (CCRT) at our institution, were screened. For each tissue, we delineated the partitions and analyzed the spatial distribution of the tumor in an in situ immune microenvironment. The density and regional characteristics of immune factor-positive cells, together with the dynamics of various cells based on treatment regimens, were considered important factors influencing the prognostic significance of cancer.</p><p><strong>Results: </strong>Compared with baseline tissues, the density of CD4 + and CD8 + T cells in the tumor microenvironment of the on-treatment tissues decreased, but the expression of IFN-γ in CD4 + and CD8 + T cells increased. The density of LAG3 positive cells was correlated significantly with the density of CD4 + and CD8 + T cells in both baseline and on-treatment tissues. The density of LAG3 + T cells and the rate of LAG3 positivity in activated CD4 + and CD8 + T cells were associated with elevated Ki67 expression. There was a significant correlation between high LAG3 expression and active CD4 + and CD8 + T cells in tumor cells. Elevated densities and tighter spatial relationships of both CD4 + and CD8 + T cells were associated with longer overall survival with ESCC.</p><p><strong>Conclusion: </strong>Concurrent chemoradiotherapy without combined immunotherapy inhibited tumor-infiltrating T cells to a certain extent, and elevated immune checkpoint LAG3 was closely associated with immune activation in the ESCC tumor microenvironment.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 7","pages":"215"},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analyses of single-cell RNA sequencing uncover the role of intratumoral Helicobacter pylori in shaping tumor progression and immunity in gastric cancer.","authors":"Jiao Xu, Jin Yang, Qi Sun, Jingbo Chang, Fan Wang","doi":"10.1007/s00262-025-04048-6","DOIUrl":"10.1007/s00262-025-04048-6","url":null,"abstract":"<p><p>The intratumoral microbiota is closely associated with tumor initiation and progression in multiple solid tumors, including gastric cancer (GC). Single-cell analysis of host-microbiome interactions (SAHMI) is a pipeline used to systematically recover and denoise microbial signals in human clinical tissues and examine tumor-microbiome interactions at the single-cell transcriptome level. In a large GC cohort, we used SAHMI to detect 12 bacteria, among which Helicobacter pylori (H. pylori) was widely present in multiple tumor and normal samples. Meanwhile, we verified the presence of H. pylori in GC tissues via fluorescence in situ hybridization and immunohistochemistry. We performed single-cell RNA sequencing to analyze 11 cell populations, including B cells, T cells, and epithelial cells, and these cell types contained large numbers of H. pylori. We detected obvious enrichment of H. pylori in cancer cells and identified 13 upregulated differentially expressed genes exhibiting significantly negative correlations with patient survival in the H. pylori-positive tumor group compared with the findings in the other groups, indicating that these genes could represent prognostic biomarkers or therapeutic targets for H. pylori-infected patients with GC. Moreover, H. pylori-enriched immune cells, including T cells, B cells, and macrophages, were associated with cell-type-specific gene expression and pathway activities, including cell fate and immune signaling. In summary, tumor-microbiome interactions might reflect or influence tumorigenesis in GC, which has implications for clinical practice.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 7","pages":"218"},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of rheumatoid factors on the function of therapeutic monoclonals specific for PD-1/PD-L1.","authors":"Barry D Hock, Liping Goddard, Lachlan J Dobson, Sean A MacPherson, John L O'Donnell, Judith L McKenzie, Alexander D McLellan","doi":"10.1007/s00262-025-04078-0","DOIUrl":"10.1007/s00262-025-04078-0","url":null,"abstract":"<p><p>The efficacy of blocking antibodies against programmed death-1 (PD-1) and its ligand (PD-L1) is modulated by signalling through their Fc regions. The Fc region of anti-PD-1/PD-L1 antibodies, when cell-bound, represents a potential target for recognition by circulating rheumatoid factor (RF) autoantibodies. The resultant cell-associated immune complex may then provide different Fc signals to that of the PD-1/PD-L1 antibodies alone. However, little is known regarding the interaction of RF and therapeutic PD-1/PD-L1 antibodies. We report that PD-1 (pembrolizumab, nivolumab) and PD-L1 (avelumab) antibodies, when bound to their cellular targets, are recognised by both IgM-RF and IgA-RF components of RF⁺ patient serum. We further demonstrate that the presence of RF provides PD-1 antibodies with the ability to induce complement-dependent cytotoxicity (CDC) of a PD-1⁺ target cell line in the presence of human complement. Although RF provided avelumab with the ability to induce CDC in assays using rabbit complement, no CDC was observed in the presence of human complement. The presence of RF did not modulate the level of Fc receptor-triggered cellular cytotoxicity or neutrophil activation that was induced by PD-1/PD-L1 antibodies alone. This study demonstrates that RF has the potential to modulate the Fc-associated signals generated following binding of PD-1/PD-L1 antibodies. The impact of RF on their efficacy therefore merits further investigation.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 7","pages":"216"},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transarterial chemoembolization combined with tyrosine kinase inhibitors and/or immune checkpoint inhibitors induced hypothyroidism is associated with improved overall survival in hepatocellular carcinoma.","authors":"Shengyuan Xu, Ruipeng Zheng, Chenghao Sun, Ri Sa","doi":"10.1007/s00262-025-04073-5","DOIUrl":"10.1007/s00262-025-04073-5","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) treatments, including transarterial chemoembolization (TACE) and systemic therapies (tyrosine kinase inhibitors [TKIs]/immune checkpoint inhibitors [ICIs]) are linked to hypothyroidism. This study aims to elucidate the clinical significance of treatment-induced hypothyroidism within a real-world cohort. We enrolled 130 HCC patients with baseline thyroid function measurements, and stratified into two cohorts: TACE monotherapy (n = 50) or TACE combined with TKIs/ICIs (n = 80). Primary subclinical or obvious hypothyroidism patients have a serum thyroid-stimulating hormone (TSH) value exceeding the upper limit of the normal range (> 4.94 uIU/L) while thyroid free tetraiodothyronine levels are normal or low. Overall survival (OS) was evaluated via Kaplan-Meier and Cox proportional models. Mortality rate in the whole study population was 25% (13/52) in patients with hypothyroidism vs. 48.7% (38/78) in patients without hypothyroidism (P = 0.007). When using TACE combining TKIs and ICIs, the mortality rate of patients with hypothyroidism were less than that of patients without hypothyroidism (16% [4/25] vs. 50% [8/16], respectively; P = 0.02). For entire cohort, the median OS cutoff in patients with hypothyroidism reached 37.5 months, and median OS was 23.33 months in patients without hypothyroidism (P = 0.015). For patients treated with TACE combined with TKIs + ICIs, the median OS cutoff in patients with hypothyroidism was not reached. But it was longer than those without hypothyroidism where median OS was 22.54 months (P = 0.005). In univariate and multivariate analysis, cancer-specific mortality correlated with some factors including sex, drinking, and hypothyroidism in the whole population as well as subgroups received TACE only or combination. In all patients, after adjustment for confounding factors, drinking showed an increased risk of HCC mortality (HR: 1.94, 95% CI: 1.04-3.61, P = 0.038) versus nondrinkers. Additionally, smoking and higher Child-Pugh score marginally associated with HCC mortality at significance levels of P = 0.042 and P = 0.041, respectively. TACE combination therapy exhibited lower risk on HCC specific mortality than those treated by TACE monotherapy group (HR: 0.45, 95% CI: 0.26-0.82, P = 0.009) among all patients receiving these therapies. Hypothyroidism was inversely related to HCC mortality among the TACE combination patients' group (HR: 0.30, 95% CI: 0.13-0.68, P = 0.04). The result becomes more pronounced in HCCs also administered by TKIs and ICIs (HR: 0.14, 95% CI: 0.03-0.60, P = 0.009). Treatment-induced hypothyroidism is prevalent among HCC patients receiving TACE combined with TKIs/ICIs and is associated with improved survival, potentially reflecting immune activation. Further multinational studies are warranted to validate these observations across diverse ethnic populations and treatment protocols.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 7","pages":"217"},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosomal PD-L1 derived from hypoxia nasopharyngeal carcinoma cell exacerbates CD8⁺ T cell suppression by promoting PD-L1 upregulation in macrophages.","authors":"Xiaofei Yuan, Xiong Liu, Di Jiang, Zijun Zheng, Xuemin Ma, Shuting Wu, Xiangping Li, Juan Lu, Ming Fu","doi":"10.1007/s00262-025-04047-7","DOIUrl":"10.1007/s00262-025-04047-7","url":null,"abstract":"<p><p>Immunotherapy targeting the programmed death ligand-1/programmed cell death protein-1 (PD-L1/PD-1) pathway exhibits limited effectiveness in individuals with recurrent and metastatic nasopharyngeal carcinoma (NPC). Recent studies have noted that hypoxia within the tumor microenvironment (TME) triggers intricate interplay, termed \"hypoxia-induced exosome-mediated communication\", between cancer cells and various immune cells. However, the role of hypoxia in modulating the immunosuppressive environment and its implications on the efficacy of immunotherapy in NPC remains poorly understood. In this study, we found hypoxia inducible factor-1 (HIF-1α) was positively associated with increased PD-L1 levels and decreased CD8⁺ T cell infiltration, and correlated with a poor prognosis. Mechanistically, we demonstrated that hypoxia regulated the expression of PD-L1 in NPC cells and their exosomes by activating the binding of HIF-1α to the PD-L1 promoter. Meanwhile, using in vitro approaches, we found that macrophages could upregulate their PD-L1 expression through the phagocytosis of exosomal PD-L1 derived from NPC cells. Furthermore, we confirmed that PD-L1⁺ macrophages could induce CD8⁺ T cell exhaustion and reduce their proliferation. In conclusion, our study revealed that hypoxia (via HIF-1α) upregulated the expression of PD-L1 in exosomes derived from NPC cells, while macrophages induce the suppression of CD8⁺ T cells by phagocytosis of exosomal PD-L1. Targeting the PD-L1⁺ macrophages could potentially serve as a promising approach to augment the effectiveness of immune checkpoint blockade in NPC.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 7","pages":"220"},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mimicry between parasites and cancer: a novel approach for developing cancer vaccines and therapeutic antibodies.","authors":"Maha Mohamed Eissa, Sonia Rifaat Ahmed Allam, Cherine Adel Ismail, Rasha Abdelmawla Ghazala, Nahla El Skhawy, Eman Ibrahim El-Said Ibrahim","doi":"10.1007/s00262-025-04069-1","DOIUrl":"10.1007/s00262-025-04069-1","url":null,"abstract":"<p><p>Cancer is one of the most dreaded diseases worldwide. Conventional treatments such as surgery, chemotherapy, and radiotherapy have limitations and adverse effects. Cancer immunotherapy and targeted therapies offer new treatment options. Parasite-based cancer therapy shows promise in fighting tumors. Some parasites have anti-cancer properties through multi-mechanistic strategies, with the molecular mimicry theory as a leading explanation for parasites' anti-cancer effects. This study aimed to explore the existence of shared antigenic proteins between parasites (Trichinella spiralis, Schistosoma mansoni, and Toxoplasma gondii) and cancer cell lines (MCF-7 human breast cancer and A549 human lung cancer). Polyclonal antisera against T. spiralis, S. mansoni, and T. gondii parasites were generated in rabbits. Antibody reactivity with extracts of MCF-7 and A549 cancer cells was detected using SDS-PAGE and immunoblotting. Results documented the molecular mimicry between parasites and cancers as it revealed cross-reactive bands when using T. spiralis antibodies against MCF-7 and A549 cancer cell extracts at approximate molecular weights of 70 and 35 kDa, and with S. mansoni antibodies at an approximate molecular weight of 80 kDa. Toxoplasma gondii antibodies neither reacted with MCF-7 human breast cancer nor A549 human lung cancer cell extracts. Results of this study could establish a foundation for subsequent investigation among a broad range of parasites for molecular mimicry with cancers. Identification, molecular characterization, and investigation of the anti-neoplastic activity of these cross-reactive antigens could shed light on new pathways for the potential development of a novel class of innovative cancer vaccine candidates and therapeutic antibodies of parasitic origin for cancer immunotherapy and targeted therapy.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 7","pages":"212"},"PeriodicalIF":0.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144121995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular subtyping dictates therapeutic response to anti-PD-L1 immunotherapy in ES-SCLC.","authors":"Qianqian Zhang, Guoxin Wang, Wenjie Yan, Dong Wang, Jie Yin, Yong Song, Mingxiang Ye, Tangfeng Lv","doi":"10.1007/s00262-025-04068-2","DOIUrl":"10.1007/s00262-025-04068-2","url":null,"abstract":"<p><p>Anti-PD-L1 immunotherapy is recommended as standard of care for patients with extensive stage small cell lung cancer (ES-SCLC); however, there are no reliable biomarkers guiding patient selection and the survival benefit of PD-L1 inhibitors in the overall population is limited. In this study, we retrospectively analyzed a total number of 61 cases of ES-SCLC who underwent anti-PD-L1 immunotherapy. Patient demographic characteristics and laboratory findings were processed for univariate and multivariate analysis. Subgrouping of SCLC was performed on IHC platform using antibodies against ASCL1, NEUROD1 and POU2F3. The tumor microenvironment (TME) of ES-SCLC was evaluated by CD8 + T cell infiltration, granzyme B production and PD-L1 expression. We found limited efficacy of defined variable factors conferring therapeutic outcomes of anti-PD-L1 immunotherapy in patients with ES-SCLC. Intriguingly, there was a profound difference in TME and response to anti-PD-L1 immunotherapy when classifying SCLC into A/N/P/I subgroups. Although accounted for a small proportion of SCLC, the SCLC-P and SCLC-I subtypes manifested as T cell-enriched \"hot\" tumor and elicited more favorable response to immunotherapy, whereas the SCLC-A and SCLC-N subgroups were T cell-absent \"cold\" tumor. There was also a significant difference in progression free survival and overall survival across these subsets. Moreover, we found the SCLC-P and SCLC-I tumors revealed features of low neuroendocrine (NE) differentiation and showed clinicopathologic features overlapping with the SCLC non-NE lineage. These findings may aid clinicians to select ES-SCLC patients who were more likely to gain higher response rate and longer survival to anti-PD-L1 immunotherapy. Revisiting SCLC according to A/N/P/I subtyping and NE/non-NE differentiation is a reliable approach to guide therapeutic strategy in patients with ES-SCLC.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 7","pages":"213"},"PeriodicalIF":0.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144121997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted CD47 checkpoint blockade using a mesothelin-directed antibody construct for enhanced solid tumor-specific immunotherapy.","authors":"Anna Reischer, Alexandra Leutbecher, Björn Hiller, Enrico Perini, Kieron White, Alejandra Hernández-Cáceres, Alexandra Schele, Benjamin Tast, Lisa Rohrbacher, Lis Winter, Bastian Czogalla, Sven Mahner, Heinrich Flaswinkel, Heinrich Leonhardt, Lorenza Wyder, Christian Wichmann, Denis Maenner, Fabian Trillsch, Mirjana Kessler, Karl-Peter Hopfner, Nadja C Fenn, Marion Subklewe","doi":"10.1007/s00262-025-04032-0","DOIUrl":"10.1007/s00262-025-04032-0","url":null,"abstract":"<p><p>The immune checkpoint CD47 is highly upregulated in several cancers as an innate immune escape mechanism. CD47 delivers a \"don't eat me\" signal to its co-receptor signal regulatory protein α (SIRPα), thereby inhibiting phagocytosis. Blocking the CD47-SIRPα axis is a promising immunotherapeutic strategy against cancer. However, early trial data has demonstrated on-target off-leukemia toxicity. In addition, the ubiquitous expression pattern of CD47 might contribute to an antigen sink. In this study, we combined low-affinity CD47 checkpoint blockade and specific tumor targeting in a multivalent and multifunctional antibody construct to prevent CD47-related toxicities. First, we established a local inhibitory checkpoint monoclonal antibody (LicMAb) by fusing two N-terminal extracellular domains of SIRPα to a full-length anti-human mesothelin (MSLN)-IgG1 antibody, a well-described tumor-associated antigen in epithelial ovarian cancer (EOC) and pancreatic ductal adenocarcinoma (PDAC). Next, we evaluated the SIRPα-αMSLN LicMAb for mediating a tumor-restricted immune response as observed by antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Our data validates CD47 and MSLN as highly upregulated targets expressed on various solid cancer entities, particularly EOC. We show tumor-specific binding and CD47 blocking by the SIRPα-αMSLN LicMAb even in the presence of healthy CD47-expressing cells. Furthermore, the LicMAb induces NK-cell-mediated cytotoxicity and improves phagocytosis of EOC and PDAC tumor cells. Moreover, cell death in EOC-derived organoids was specifically LicMAb-driven. Hence, the SIRPα-αMSLN LicMAb combines a tumor-restricted blockade of the CD47-SIRPα axis with a specific antitumor response while preventing on-target off-tumor toxicities. Our data supports the multifunctional SIRPα-αMSLN LicMAb as a promising approach to treating solid tumors.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":"74 7","pages":"214"},"PeriodicalIF":0.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144121999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Divergent prognostic effects of pre-existing and treatment-emergent thyroid dysfunction in patients treated with immune checkpoint inhibitors.","authors":"Mitchell S von Itzstein,&nbsp;Amrit S Gonugunta,&nbsp;Yiqing Wang,&nbsp;Thomas Sheffield,&nbsp;Rong Lu,&nbsp;Sadia Ali,&nbsp;Farjana J Fattah,&nbsp;Donglu Xie,&nbsp;Jennifer Cai,&nbsp;Yang Xie,&nbsp;David E Gerber","doi":"10.1007/s00262-022-03151-2","DOIUrl":"https://doi.org/10.1007/s00262-022-03151-2","url":null,"abstract":"<p><strong>Background: </strong>Thyroid dysfunction is among the most common autoimmune diseases and immune checkpoint inhibitor (ICI)-induced immune-related adverse events (irAE). We determined the association between longitudinal thyroid function and clinical outcomes in patients treated with ICI.</p><p><strong>Methods: </strong>We identified all patients treated with ICI at UT Southwestern Medical Center from January 1, 2011, through December 31, 2020. We defined normal thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels according to institutional reference range. We defined clinical thyroid dysfunction using established criteria incorporating labs and treatment. We determined the association between thyroid function and overall survival (OS) using Kaplan-Meier curves, log-rank tests, and multivariate Cox proportional hazards model.</p><p><strong>Results: </strong>A total of 1781 patients were included in analyses, of whom 381 (21%) had abnormal baseline TSH. Patients with abnormal baseline TSH were more likely to be female, have kidney cancer, and initiate levothyroxine after ICI initiation (all P < 0.001). Patients with abnormal baseline TSH had inferior OS (median 16 vs 27 months; P < 0.001). Among patients with normal baseline TSH, those who had abnormal TSH after ICI initiation had improved OS (median 41 vs 22 months; P < 0.001). In a multivariate Cox model, abnormal baseline TSH was associated with worse OS (HR 1.62; 95% CI, 1.30-2.02; P < 0.001), while initiation of levothyroxine after ICI initiation was associated with improved OS (HR 0.62; 95% CI, 0.44-0.88; P = 0.008).</p><p><strong>Conclusions: </strong>ICI-induced thyroid dysfunction is associated with improved survival, although abnormal TSH prior to ICI initiation is associated with inferior survival.</p><p><strong>Precis: </strong>Thyroid abnormalities occur commonly in the general population and as immunotherapy toxicities. We found that immunotherapy-induced thyroid dysfunction is associated with better survival, but pre-existing thyroid abnormalities convey worse outcomes.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":"2169-2181"},"PeriodicalIF":5.8,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9308834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39854791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}