Cancer Immunology, Immunotherapy最新文献

{"title":"NKG2D-bispecific enhances NK and CD8+ T cell antitumor immunity.","authors":"Aurelie Herault, Judy Mak, Josefa de la Cruz-Chuh, Michael A Dillon, Diego Ellerman, MaryAnn Go, Ely Cosino, Robyn Clark, Emily Carson, Stacey Yeung, Melanie Pichery, Mylène Gador, Eugene Y Chiang, Jia Wu, Yuxin Liang, Zora Modrusan, Gautham Gampa, Jawahar Sudhamsu, Christopher C Kemball, Victoria Cheung, Thi Thu Thao Nguyen, Dhaya Seshasayee, Robert Piskol, Klara Totpal, Shang-Fan Yu, Genee Lee, Katherine R Kozak, Christoph Spiess, Kevin B Walsh","doi":"10.1007/s00262-024-03795-2","DOIUrl":"10.1007/s00262-024-03795-2","url":null,"abstract":"<p><strong>Background: </strong>Cancer immunotherapy approaches that elicit immune cell responses, including T and NK cells, have revolutionized the field of oncology. However, immunosuppressive mechanisms restrain immune cell activation within solid tumors so additional strategies to augment activity are required.</p><p><strong>Methods: </strong>We identified the co-stimulatory receptor NKG2D as a target based on its expression on a large proportion of CD8+ tumor infiltrating lymphocytes (TILs) from breast cancer patient samples. Human and murine surrogate NKG2D co-stimulatory receptor-bispecifics (CRB) that bind NKG2D on NK and CD8+ T cells as well as HER2 on breast cancer cells (HER2-CRB) were developed as a proof of concept for targeting this signaling axis in vitro and in vivo.</p><p><strong>Results: </strong>HER2-CRB enhanced NK cell activation and cytokine production when co-cultured with HER2 expressing breast cancer cell lines. HER2-CRB when combined with a T cell-dependent-bispecific (TDB) antibody that synthetically activates T cells by crosslinking CD3 to HER2 (HER2-TDB), enhanced T cell cytotoxicity, cytokine production and in vivo antitumor activity. A mouse surrogate HER2-CRB (mHER2-CRB) improved in vivo efficacy of HER2-TDB and augmented NK as well as T cell activation, cytokine production and effector CD8+ T cell differentiation.</p><p><strong>Conclusion: </strong>We demonstrate that targeting NKG2D with bispecific antibodies (BsAbs) is an effective approach to augment NK and CD8+ T cell antitumor immune responses. Given the large number of ongoing clinical trials leveraging NK and T cells for cancer immunotherapy, NKG2D-bispecifics have broad combinatorial potential.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 10","pages":"209"},"PeriodicalIF":4.6,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11306676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901084","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":"DNA hypo-methylation and expression of GBP4 induces T cell exhaustion in pancreatic cancer.","authors":"Yesiboli Tasiheng, Xuan Lin, Xu Wang, Xuan Zou, Yusheng Chen, Yu Yan, Mingjian Ma, Zhengjie Dai, Xu Wang, Xianjun Yu, He Cheng, Chen Liu","doi":"10.1007/s00262-024-03786-3","DOIUrl":"10.1007/s00262-024-03786-3","url":null,"abstract":"<p><p>Immunotherapy for pancreatic ductal carcinoma (PDAC) remains disappointing due to the repressive tumor microenvironment and T cell exhaustion, in which the roles of interferon-stimulated genes were largely unknown. Here, we focused on a typical interferon-stimulated gene, GBP4, and investigated its potential diagnostic and therapeutic value in pancreatic cancer. Expression analysis on both local samples and public databases indicated that GBP4 was one of the most dominant GBP family members present in the PDAC microenvironment, and the expression level of GBP4 was negatively associated with patient survival. We then identified DNA hypo-methylation in regulatory regions of GBP4 in PDAC, and validated its regulatory role on GBP4 expression via performing targeted methylation using dCas9-SunTag-DNMAT3A-sgRNA-targeted methylation system on selected DNA locus. After that, we investigated the downstream functions of GBP4, and chemotaxis assays indicated that GBP4 overexpression significantly improved the infiltration of CD8⁺T cells, but also induced upregulation of immune checkpoint genes and T cell exhaustion. Lastly, in vitro T cell killing assays using primary organoids suggested that the PDAC samples with high level of GBP4 expression displayed significantly higher sensitivity to anti-PD-1 treatment. Taken together, our studies revealed the expression patterns and epigenetic regulatory mechanisms of GBP4 in pancreatic cancer and clarified the effects of GBP4 on T cell exhaustion and antitumor immunology.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 10","pages":"208"},"PeriodicalIF":4.6,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11306721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896862","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 PI3K-gamma in myeloid driven tumour immune suppression: a systematic review and meta-analysis of the preclinical literature.","authors":"Haonan Xu, Shannon Nicole Russell, Katherine Steiner, Eric O'Neill, Keaton Ian Jones","doi":"10.1007/s00262-024-03779-2","DOIUrl":"10.1007/s00262-024-03779-2","url":null,"abstract":"<p><p>The intricate interplay between immune and stromal cells within the tumour microenvironment (TME) significantly influences tumour progression. Myeloid cells, including tumour-associated macrophages (TAMs), neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs), contribute to immune suppression in the TME (Nakamura and Smyth in Cell Mol Immunol 17(1):1-12 (2020). https://doi.org/10.1038/s41423-019-0306-1 ; DeNardo and Ruffell in Nat Rev Immunol 19(6):369-382 (2019). https://doi.org/10.1038/s41577-019-0127-6 ). This poses a significant challenge for novel immunotherapeutics that rely on host immunity to exert their effect. This systematic review explores the preclinical evidence surrounding the inhibition of phosphoinositide 3-kinase gamma (PI3Kγ) as a strategy to reverse myeloid-driven immune suppression in solid tumours. EMBASE, MEDLINE, and PubMed databases were searched on 6 October 2022 using keyword and subject heading terms to capture relevant studies. The studies, focusing on PI3Kγ inhibition in animal models, were subjected to predefined inclusion and exclusion criteria. Extracted data included tumour growth kinetics, survival endpoints, and immunological responses which were meta-analysed. PRISMA and MOOSE guidelines were followed. A total of 36 studies covering 73 animal models were included in the review and meta-analysis. Tumour models covered breast, colorectal, lung, skin, pancreas, brain, liver, prostate, head and neck, soft tissue, gastric, and oral cancer. The predominant PI3Kγ inhibitors were IPI-549 and TG100-115, demonstrating favourable specificity for the gamma isoform. Combination therapies, often involving chemotherapy, radiotherapy, immune checkpoint inhibitors, biological agents, or vaccines, were explored in 81% of studies. Analysis of tumour growth kinetics revealed a statistically significant though heterogeneous response to PI3Kγ monotherapy, whereas the tumour growth in combination treated groups were more consistently reduced. Survival analysis showed a pronounced increase in median overall survival with combination therapy. This systematic review provides a comprehensive analysis of preclinical studies investigating PI3Kγ inhibition in myeloid-driven tumour immune suppression. The identified studies underscore the potential of PI3Kγ inhibition in reshaping the TME by modulating myeloid cell functions. The combination of PI3Kγ inhibition with other therapeutic modalities demonstrated enhanced antitumour effects, suggesting a synergistic approach to overcome immune suppression. These findings support the potential of PI3Kγ-targeted therapies, particularly in combination regimens, as a promising avenue for future clinical exploration in diverse solid tumour types.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 10","pages":"204"},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892921","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":"The expression of PD-L1 on tumor-derived exosomes enhances infiltration and anti-tumor activity of αCD3 × αPD-L1 bispecific antibody-armed T cells.","authors":"Jaewon Cho, Nara Tae, Yujeong Song, Chae-Won Kim, Seung-Joo Lee, Jae-Hee Ahn, Kwang-Ho Lee, Byung-Hyun Lee, Byung Soo Kim, Sun-Young Chang, Dae Hee Kim, Hyun-Jeong Ko","doi":"10.1007/s00262-024-03785-4","DOIUrl":"10.1007/s00262-024-03785-4","url":null,"abstract":"<p><p>Anti-cluster of differentiation (CD) 3 × α programmed death-ligand 1 (PD-L1) bispecific T-cell engager (BsTE)-bound T-cells (BsTE:T) are a promising new cancer treatment agent. However, the mechanisms of action of bispecific antibody-armed activated T-cells are poorly understood. Therefore, this study aimed to investigate the anti-tumor mechanism and efficacy of BsTE:T. The BsTE:T migration was assessed in vivo and in vitro using syngeneic and xenogeneic tumor models, flow cytometry, immunofluorescence staining, transwell migration assays, microfluidic chips, Exo View R100, western blotting, and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 technology. In murine B16 melanoma, MC38 colon cancer, and human multiple myeloma cells, BsTE:T exhibited superior tumor elimination relative to that of T-cells or BsTE alone. Moreover, BsTE:T migration into tumors was significantly enhanced owing to the presence of PD-L1 in tumor cells and secretion of PD-L1-containing exosomes. Furthermore, increased infiltration of CD44^highCD62L^low effector memory CD8⁺ T-cells into tumors was closely associated with the anti-tumor effect of BsTE:T. Therefore, BsTE:T is an innovative potential anti-tumor therapy, and exosomal PD-L1 plays a crucial role both in vitro and in vivo in the anti-tumor activity of BsTE:T.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 10","pages":"196"},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892922","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":"First-line treatment with KN046, chemotherapy and palliative radiotherapy for advanced esophageal squamous cell carcinoma: an open-label, dose escalation, and dose expansion phase Ib trial.","authors":"Qi Zhao, Xi Su, Jiao Xue, Yandong Liu, Jiaxing Zhu, Xuwei Cai, Songbing Qin","doi":"10.1007/s00262-024-03769-4","DOIUrl":"10.1007/s00262-024-03769-4","url":null,"abstract":"<p><p>There is growing evidence to suggest that radiotherapy might enhance the efficacy of immunotherapy. This study aimed to assess the possibility of KN046, a bispecific antibody targeting PD-L1 and CTLA-4, combined with chemotherapy and palliative radiotherapy for advanced esophageal squamous cell carcinoma (ESCC). In this open-label, phase Ib trial, patients with advanced ESCC were administered chemotherapy with palliative radiotherapy, and KN046 in the predefined escalation dosages of 1, 3, or 5 mg/kg (every 3 weeks during chemotherapy cycles and every 2 weeks during KN046 maintenance). The chemotherapy regimen constituted cisplatin (75 mg/m² i.v., d1) and paclitaxel (135-175 mg/m² ivgtt., d1). Radiotherapy specifics, including site, timing, dose, and fragmentation pattern, were at the investigator's discretion. The primary outcome was dose-limiting toxicity (DLT). From May 2019 to April 2021, 25 patients were enrolled across the dosage groups: 3 in 1 mg/kg, 12 in 3 mg/kg, and 10 in 5 mg/kg. No DLT was observed during the dose escalation. The objective response rate was 41.7% (95%CI 22.1-63.4), while the disease control rate was 87.5% (95%CI 67.6-97.3). At a median follow-up of 11.8 months, the median progression-free survival was 7.8 months (95%CI 5.2-9.7) and median overall survival was 15.9 months (95%CI 8.4-NE). Serious adverse events were reported in 48.0% of patients, predominantly leukopenia (16%), immune-mediated enterocolitis (12%), immune-mediated pneumonitis (8%), and neutropenia (8%). Combining KN046 with chemotherapy and palliative radiotherapy might be feasible, showing a favorable safety profile and notable efficacy in advanced ESCC patients.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 10","pages":"194"},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892968","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":"Genomic and transcriptomic profiles associated with response to eribulin and nivolumab combination in HER-2-negative metastatic breast cancer.","authors":"Changhee Park, Koung Jin Suh, Se Hyun Kim, Kyung-Hun Lee, Seock-Ah Im, Min Hwan Kim, Joohyuk Sohn, Jae Ho Jeong, Kyung Hae Jung, Kyoung Eun Lee, Yeon Hee Park, Hee-Jun Kim, Eun Kyung Cho, In Sil Choi, Seung-Jae Noh, Inkyung Shin, Dae-Yeon Cho, Jee Hyun Kim","doi":"10.1007/s00262-024-03782-7","DOIUrl":"10.1007/s00262-024-03782-7","url":null,"abstract":"<p><strong>Background: </strong>Biomarkers for predicting response to the immunotherapy and chemotherapy combination in breast cancer patients are not established. In this study, we report exploratory genomic and transcriptomic analyses of pretreatment tumor tissues from patients enrolled in phase II clinical trial of a combination of eribulin and nivolumab for HER-2-negative metastatic breast cancer (MBC) (KORNELIA trial, NCT04061863).</p><p><strong>Methods: </strong>We analyzed associations between tumor molecular profiles based on genomic (n = 76) and transcriptomic data (n = 58) and therapeutic efficacy. Patients who achieved progression-free survival (PFS) ≥ 6 months were defined as PFS6-responders and PFS6-nonresponders otherwise.</p><p><strong>Findings: </strong>Analyses on tumor mutation burden (TMB) showed a tendency toward a favorable effect on efficacy, while several analyses related to homologous recombination deficiency (HRD) indicated a potentially negative impact on efficacy. Patients harboring TP53 mutations showed significantly poor PFS6 rate and PFS, which correlated with the enrichment of cell cycle-related signatures in PFS6-nonresponders. High antigen presentation gene set enrichment scores (≥ median) were significantly associated with longer PFS. Naïve B-cell and plasma cell proportions were considerably higher in long responders (≥ 18 months).</p><p><strong>Interpretation: </strong>Genomic features including TMB, HRD, and TP53 mutations and transcriptomic features related to immune cell profiles and cell cycle may distinguish responders. Our findings provide insights for further exploring the combination regimen and its biomarkers in these tumors.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 10","pages":"197"},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892969","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":"Unlocking the potential of HHLA2: identifying functional immune infiltrating cells in the tumor microenvironment and predicting clinical outcomes in laryngeal squamous cell carcinoma.","authors":"Wenjing Li, Jianqing You, Haixiang Xue, Yi Liu, Junjun Chen, Xiao Zheng, Lujun Chen, Changping Wu","doi":"10.1007/s00262-024-03791-6","DOIUrl":"10.1007/s00262-024-03791-6","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;HHLA2 (human endogenous retrovirus-H long terminal repeat-associating protein 2) represents a recently identified member of the B7 immune checkpoint family, characterized by limited expression in normal tissues but notable overexpression in various cancer types. Nevertheless, the precise function and interaction with immune cells remain poorly understood, particularly in laryngeal squamous cell carcinoma (LSCC). This investigation endeavored to elucidate the biological significance of HHLA2 within the tumor microenvironment of human LSCC tissues and delineate the clinical relevance and functional roles of HHLA2 in LSCC pathogenesis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Through multiplexed immunohistochemistry analyses conducted on tissue microarrays sourced from LSCC patients (n = 72), the analysis was executed to assess the expression levels of HHLA2, density and spatial patterns of CD68&lt;sup&gt;+&lt;/sup&gt;HLA-DR&lt;sup&gt;+&lt;/sup&gt;CD163&lt;sup&gt;-&lt;/sup&gt; (M1 macrophages), CTLA-4&lt;sup&gt;+&lt;/sup&gt;CD4&lt;sup&gt;+&lt;/sup&gt;FoxP3&lt;sup&gt;+&lt;/sup&gt; (CTLA-4&lt;sup&gt;+&lt;/sup&gt;Treg cells), CTLA-4&lt;sup&gt;+&lt;/sup&gt;CD4&lt;sup&gt;+&lt;/sup&gt;FoxP3&lt;sup&gt;-&lt;/sup&gt; (CTLA-4&lt;sup&gt;+&lt;/sup&gt;Tcon cells), exhausted CD8&lt;sup&gt;+&lt;/sup&gt;T cells, and terminally exhausted CD8&lt;sup&gt;+&lt;/sup&gt;T cells in LSCC tissues. Survival analysis was conducted to evaluate the prognostic significance of HHLA2 and these immune checkpoints or immune cell populations, employing COX regression analysis to identify independent prognostic factors.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Kaplan-Meier (K-M) survival curves revealed a significant association between HHLA2 expression and overall survival (OS) in LSCC. Elevated levels of HHLA2 were linked to reduced patient survival, indicating its potential as a prognostic marker (HR: 3.230, 95%CI 0.9205-11.34, P = 0.0067). Notably, increased infiltration of CD68&lt;sup&gt;+&lt;/sup&gt; cells (total macrophages), STING&lt;sup&gt;+&lt;/sup&gt;CD68&lt;sup&gt;+&lt;/sup&gt;HLA-DR&lt;sup&gt;+&lt;/sup&gt;CD163&lt;sup&gt;-&lt;/sup&gt; (STING&lt;sup&gt;+&lt;/sup&gt;M1 macrophages), CTLA-4&lt;sup&gt;+&lt;/sup&gt;CD4&lt;sup&gt;+&lt;/sup&gt;FoxP3&lt;sup&gt;+&lt;/sup&gt;, CTLA-4&lt;sup&gt;+&lt;/sup&gt;CD4&lt;sup&gt;+&lt;/sup&gt;FoxP3&lt;sup&gt;-&lt;/sup&gt;, PD-1&lt;sup&gt;+&lt;/sup&gt;LAG-3&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt;T cells, and PD-1&lt;sup&gt;+&lt;/sup&gt;LAG-3&lt;sup&gt;+&lt;/sup&gt;TIM-3&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt;T cells strongly linked to poorer survival outcomes (P &lt; 0.05). A discernible trend was observed between the levels of these immune cell populations, STING&lt;sup&gt;+&lt;/sup&gt;CD68&lt;sup&gt;+&lt;/sup&gt; (STING&lt;sup&gt;+&lt;/sup&gt; total macrophages), CD68&lt;sup&gt;+&lt;/sup&gt;HLA-DR&lt;sup&gt;+&lt;/sup&gt;CD163&lt;sup&gt;-&lt;/sup&gt;, STING&lt;sup&gt;+&lt;/sup&gt;CD68&lt;sup&gt;+&lt;/sup&gt;CD163&lt;sup&gt;+&lt;/sup&gt;HLA-DR&lt;sup&gt;-&lt;/sup&gt; (STING&lt;sup&gt;+&lt;/sup&gt;M2 macrophages), PD-1&lt;sup&gt;+&lt;/sup&gt;LAG-3&lt;sup&gt;-&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt;T cells, PD-1&lt;sup&gt;+&lt;/sup&gt;TIM-3&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt;T cells, and PD-1&lt;sup&gt;+&lt;/sup&gt;LAG-3&lt;sup&gt;+&lt;/sup&gt;TIM-3&lt;sup&gt;-&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt;T cells and prognosis. Importantly, multivariate COX analysis identified HHLA2 as an independent predictive factor for OS in LSCC patients (HR = 3.86, 95% CI 1.08-13.80, P = 0.038). This underscored the potential of HHLA2 as a c","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 10","pages":"207"},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892924","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":"Deciphering the interplay of HPV infection, MHC-II expression, and CXCL13⁺ CD4⁺ T cell activation in oropharyngeal cancer: implications for immunotherapy.","authors":"Shida Yan, Xing Zhang, Qiaohong Lin, Mingyuan Du, Yiqi Li, Shuai He, Jingtao Chen, Xiyuan Li, Jinxin Bei, Shuwei Chen, Ming Song","doi":"10.1007/s00262-024-03789-0","DOIUrl":"10.1007/s00262-024-03789-0","url":null,"abstract":"<p><strong>Background: </strong>Human papillomavirus (HPV) infection has become an important etiological driver of oropharyngeal squamous cell carcinoma (OPSCC), leading to unique tumor characteristics. However, the interplay between HPV-associated tumor cells and tumor microenvironment (TME) remains an enigma.</p><p><strong>Methods: </strong>We performed a single-cell RNA-sequencing (scRNA-seq) on HPV-positive (HPV⁺) and HPV-negative (HPV^‒) OPSCC tumors, each for three samples, and one normal tonsil tissue. Ex vivo validation assays including immunofluorescence staining, cell line co-culture, and flow cytometry analysis were used to test specific subtypes of HPV⁺ tumor cells and their communications with T cells.</p><p><strong>Results: </strong>Through a comprehensive single-cell transcriptome analysis, we uncover the distinct transcriptional signatures between HPV⁺ and HPV^‒ OPSCC. Specifically, HPV⁺ OPSCC tumor cells manifest an enhanced interferon response and elevated expression of the major histocompatibility complex II (MHC-II), potentially bolstering tumor recognition and immune response. Furthermore, we identify a CXCL13⁺CD4⁺ T cell subset that exhibits dual features of both follicular and pro-inflammatory helper T cells. Noteworthily, HPV⁺ OPSCC tumor cells embrace extensive intercellular communications with CXCL13⁺CD4⁺ T cells. Interaction with HPV⁺ OPSCC tumor cells amplifies CXCL13 and IFNγ release in CD4⁺T cells, fostering a pro-inflammatory TME. Additionally, HPV⁺ tumor cells expressing high MHC-II and CXCL13⁺CD4⁺ T cell prevalence are indicative of favorable overall survival rates in OPSCC patients.</p><p><strong>Conclusions: </strong>Together, our study underscores a synergistic inflammatory immune response orchestrated by highly immunogenic tumor cells and CXCL13⁺CD4⁺ T cells in HPV⁺ OPSCC, offering useful insights into strategy development for patient stratification and effective immunotherapy in OPSCC.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 10","pages":"206"},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892967","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":"Impact of the interval between neoadjuvant immunotherapy and surgery on prognosis in esophageal squamous cell carcinoma (ESCC): a real-world study.","authors":"Guozhen Yang, Yutong Hong, Xiaomin Zhang, Chufeng Zeng, Linyu Tan, Xu Zhang","doi":"10.1007/s00262-024-03787-2","DOIUrl":"10.1007/s00262-024-03787-2","url":null,"abstract":"<p><strong>Background: </strong>The time interval between neoadjuvant immunotherapy and surgery is 6 weeks for esophageal squamous cell carcinoma (ESCC), but whether delayed surgery affects prognosis remains unclear.</p><p><strong>Methods: </strong>Clinical data of locally advanced ESCC who underwent neoadjuvant immunotherapy followed by esophagectomy from November 2019 to December 2022 were collected. The surgery outcomes and prognosis were compared between short-interval (time to surgery ≤ 6 weeks) and long-interval groups (time to surgery > 6 weeks).</p><p><strong>Results: </strong>152 patients were enrolled totally, with a ratio of 91:61 between short-interval and long-interval groups. The rate of pathological complete response in the short-interval and long-interval groups were 34.1% and 24.6% (P = 0.257). Delayed surgery did not have a significantly impact on the number of lymph node dissections (P = 0.133), operative duration (P = 0.689), blood loss (P = 0.837), hospitalization duration (P = 0.293), chest drainage duration (P = 0.886) and postoperative complications (P > 0.050). The 3-year Overall survival (OS) rates were 85.10% in the short-interval group, and 82.07% in the long-interval group (P = 0.435). The 3-year disease-free survival (DFS) rates were 83.41% and 70.86% in the two groups (P = 0.037). Subgroup analysis revealed that patients with a favorable response to immunotherapy (tumor regression grade 0) exhibited inferior 3-year OS (long-interval vs. short-interval: 51.85% vs. 91.08%, P = 0.035) and DFS (long-interval vs. short-interval: 47.40% vs. 91.08%, P = 0.014) in the long-interval group.</p><p><strong>Conclusions: </strong>Delayed surgery after neoadjuvant immunotherapy does not further improve pathological response; instead, it resulted in a poorer DFS. Especially for patients with a favorable response to immunotherapy, delayed surgery increases the risk of mortality and recurrence.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 10","pages":"202"},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892972","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":"Chimeric antigen receptor dendritic cells targeted delivery of a single tumoricidal factor for cancer immunotherapy.","authors":"Rong Duan, Philip Milton, Chutamath Sittplangkoon, Xin Liu, Zhining Sui, Brendan F Boyce, Zhenqiang Yao","doi":"10.1007/s00262-024-03788-1","DOIUrl":"10.1007/s00262-024-03788-1","url":null,"abstract":"<p><strong>Background: </strong>Chimeric antigen receptor (CAR)-T cells have been used to treat blood cancers by producing a wide variety of cytokines. However, they are not effective in treating solid cancers and can cause severe side-effects, including cytokine release syndrome. TNFα is a tumoricidal cytokine, but it markedly increases the protein levels of cIAP1 and cIAP2, the members of inhibitor of apoptosis protein (IAP) family of E3 ubiquitin ligase that limits caspase-induced apoptosis. Degradation of IAP proteins by an IAP antagonist does not effectively kill cancer cells but enables TNFα to strongly induce cancer cell apoptosis. It would be a promising approach to treat cancers by targeted delivery of TNFα through an inactive adoptive cell in combination with an IAP antagonist.</p><p><strong>Methods: </strong>Human dendritic cells (DCs) were engineered to express a single tumoricidal factor, TNFα, and a membrane-anchored Mucin1 antibody scFv, named Mucin 1 directed DCs expressing TNFα (M-DCs^TNF). The efficacy of M-DCs^TNF in recognizing and treating breast cancer was tested in vitro and in vivo.</p><p><strong>Results: </strong>Mucin1 was highly expressed on the surface of a wide range of human breast cancer cell lines. M-DCs^TNF directly associated with MDA-MB-231 cells in the bone of NSG mice. M-DCs^TNF plus an IAP antagonist, SM-164, but neither alone, markedly induce MDA-MB-231 breast cancer cell apoptosis, which was blocked by TNF antibody. Importantly, M-DCs^TNF combined with SM-164, but not SM-164 alone, inhibited the growth of patient-derived breast cancer in NSG mice.</p><p><strong>Conclusion: </strong>An adoptive cell targeting delivery of TNFα combined with an IAP antagonist is a novel effective approach to treat breast cancer and could be expanded to treat other solid cancers. Unlike CAR-T cell, this novel adoptive cell is not activated to produce a wide variety of cytokines, except for additional overexpressed TNF, and thus could avoid the severe side effects such as cytokine release syndrome.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 10","pages":"203"},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892964","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}