Journal for Immunotherapy of Cancer最新文献

{"title":"Targeting MARCO in combination with anti-CTLA-4 leads to enhanced melanoma regression and immune cell infiltration via macrophage reprogramming.","authors":"Hidenori Takahashi, Patricio Perez-Villarroel, Rana Falahat, James J Mulé","doi":"10.1136/jitc-2024-011030","DOIUrl":"https://doi.org/10.1136/jitc-2024-011030","url":null,"abstract":"<p><strong>Background: </strong>Strategies to improve the therapeutic efficacy of cancer immunotherapy with immune checkpoint inhibitors include targeting additional immunosuppressive compartments in the tumor microenvironment (TME). Inhibitory macrophages (Mφ) can be one of the most abundant immune cells in the TME associated with poor prognosis. However, to date, selective Mφ depletion strategies as a cancer immunotherapy have not been successful in clinical trials. Macrophage Receptor with Collagenous Structure (MARCO) is one of a family of class-A scavenger receptors expressed by Mφ in the TME and is one of the most upregulated transcripts in dendritic cells (DC) following their ex vivo uptake of dead tumor cells. The clinical significance of MARCO expression in the TME is not fully understood.</p><p><strong>Methods: </strong>The therapeutic potential of targeting MARCO by an anti-murine MARCO (ED31, clone ED31) monoclonal antibody, which inhibits ligand-binding to MARCO, was explored in combination with anti-cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) or anti-programmed cell death protein-1 (anti-PD-1) in C57BL/6J mice bearing B16F10 or Pan02 tumors. The mechanism by which ED31 impacts the TME was investigated by flow cytometry in the different treatment arms. The contribution of Mφ was assessed by both in vivo depletion and in vitro functional assays. Chemokine production was measured by a bead-based multiplex assay.</p><p><strong>Results: </strong>ED31 enhanced antitumor efficacy of anti-CTLA-4, but not of anti-PD-1. Analysis of the TME revealed that adding ED31 to anti-CTLA-4 substantially increased immune cell infiltration, including mature conventional DC recruitment, that was due to a switch to M1-pattern chemokines by Mφ. Mφ depletion completely abrogated both the increase in immune cell infiltration and chemokine production, and abolished the antitumor efficacy of the combination therapy.</p><p><strong>Conclusions: </strong>Targeting MARCO as an additional checkpoint in the TME can offer a strategy to improve the antitumor efficacy of anti-CTLA-4 through a mechanism involving Mφ reprogramming rather than their depletion.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase 2 study of neoadjuvant durvalumab plus docetaxel, oxaliplatin, and S-1 with surgery and adjuvant durvalumab plus S-1 for resectable locally advanced gastric cancer.","authors":"Yoon-Koo Kang, Hyung-Don Kim, Hyungwoo Cho, Young Soo Park, Jong Seok Lee, Min-Hee Ryu","doi":"10.1136/jitc-2024-010635","DOIUrl":"https://doi.org/10.1136/jitc-2024-010635","url":null,"abstract":"<p><strong>Background: </strong>Based on the phase 3 PRODIGY study, neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) have emerged as a viable treatment option for Asian patients with resectable locally advanced gastric cancer (LAGC). This phase 2 study evaluated the efficacy and safety of combining neoadjuvant durvalumab with DOS, followed by surgery and adjuvant durvalumab plus S-1 chemotherapy, for resectable LAGC.</p><p><strong>Methods: </strong>Patients with LAGC with cT2/3N+or cT4Nany tumors were enrolled in this study. Patients with proficient mismatch repair protein (pMMR) tumors received three cycles of neoadjuvant durvalumab plus DOS, administered every 3 weeks, followed by surgery and adjuvant S-1 plus durvalumab (main study arm). The primary endpoints were the rate of pathologic complete regression (pCR) and safety. An exploratory arm evaluated patients with deficient mismatch repair protein (dMMR) tumors, who received three cycles of neoadjuvant durvalumab and tremelimumab, followed by surgery and adjuvant durvalumab.</p><p><strong>Results: </strong>In the main study arm, 50 pMMR patients were enrolled, and received at least one dose of neoadjuvant treatment. The median age was 63 years, with 72.0% being men. 18 and 32 patients presented with clinical stage II and III tumors, respectively. 49 (98.0%) underwent surgery, with 45 achieving R0 resection. A pCR rate of 30.0% was observed, meeting the prespecified primary efficacy endpoint. With a median follow-up of 21.8 months, the 3-year progression-free survival and overall survival rates were 69.9% and 88.1%, respectively. 10% of patients experienced predefined unacceptable severe toxicities, including febrile neutropenia (n=3) and persistent G4 neutropenia (n=2) lasting more than 7 days, thereby meeting the primary safety endpoint. Nine patients with dMMR tumors were enrolled in the exploratory arm. All nine underwent surgery, with a pCR rate of 22.2%.</p><p><strong>Conclusions: </strong>This study met its primary efficacy and safety endpoints. The combination of neoadjuvant durvalumab plus DOS, followed by surgery and adjuvant durvalumab plus S-1 chemotherapy, warrants further investigation in a phase 3 trial for Asian patients with LAGC.</p><p><strong>Clinical trial information: </strong>04221555.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potent and durable control of mesothelin-expressing tumors by a novel T cell-secreted bi-specific engager.","authors":"Paris Kosti, Johan Abram-Saliba, Laetitia Pericou-Troquier, Sarah Pavelot, Tiphaine Ruggeri, Marc Laffaille, Melita Irving, George Coukos, Evripidis Lanitis, Steven M Dunn","doi":"10.1136/jitc-2024-010063","DOIUrl":"https://doi.org/10.1136/jitc-2024-010063","url":null,"abstract":"<p><strong>Background: </strong>The glycosylphosphatidylinositol-anchored cell surface protein mesothelin (MSLN) shows elevated expression in many malignancies and is an established clinical-stage target for antibody-directed therapeutic strategies. Of these, the harnessing of autologous patient T cells via engineered anti-MSLN chimeric antigen receptors (CAR-T) is an approach garnering considerable interest. Although generally shown to target tumor MSLN safely, CAR-T trials have failed to deliver the impressive curative or response metrics achieved for hematological malignancies using the same technology. A need exists, therefore, for improved anti-MSLN molecules and/or more optimal ways to leverage immune effector cells.</p><p><strong>Methods: </strong>We performed ELISA, label-free kinetic binding assays, FACS, Western blotting, and transient recombinant MSLN expression to characterize the recognition properties of a novel CAR-active human scFv clone, LABC-13F08. To investigate T cell redirection, we conducted kinetic IncuCyte co-culture killing assays using transduced primary T cells and MSLN⁺ target cell lines and assessed levels of activation markers and effector cytokines. The antitumor potential of LABC-13F08 formatted as a bispecific engager (BiTE) was evaluated in vivo using transduced human primary T cells and immunocompromised NSG mice xenografted with ovarian, mesothelioma, and pancreatic MSLN⁺ tumor cell lines.</p><p><strong>Results: </strong>The LABC-13F08 scFv is highly unusual and distinct from existing (pre)clinical anti-MSLN antibody fragments, exhibiting an absolute requirement for divalent cations to drive MSLN recognition. As a monovalent BiTE, LABC-13F08 demonstrates robust in vitro potency. Additionally, primary human T cells engineered for constitutive secretion of the 13F08 BiTE exhibit strong antitumor activity toward in vivo ovarian and mesothelioma xenograft models and show encouraging levels of monotherapy control in a challenging pancreatic model. LABC-13F08 BiTE secreted from engineered T cells (BiTE-T) can both recruit non-engineered bystander T cells and also induce activation-dependent MSLN-independent bystander killing of cells lacking cognate antigen. To address safety concerns, 13F08 BiTE-T cells can be rapidly targeted for clearance via a molecular \"off\" switch.</p><p><strong>Conclusions: </strong>The novel LABC-13F08 scFv exhibits a mode of binding to MSLN which is not observed in typical anti-MSLN antibodies. Efficacious targeting by a T cell secreted engager would represent a clinically differentiated approach for the treatment of MSLN⁺ tumors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging T cell co-stimulation for enhanced therapeutic efficacy of trispecific antibodies targeting prostate cancer.","authors":"Yanping Sun, Linling Zhou, Xinyu Gu, Jiaqi Zhao, Jie Bi, Liqiang Pan","doi":"10.1136/jitc-2024-010140","DOIUrl":"https://doi.org/10.1136/jitc-2024-010140","url":null,"abstract":"<p><strong>Background: </strong>Clinical trials have demonstrated the efficacy of bispecific antibodies in eliciting potent antitumor responses by redirecting T cells to target cancer cells, particularly for the treatment of hematologic malignancies. However, their efficacy against solid tumors is limited by intratumoral T-cell dysfunction and inadequate persistence. The co-stimulatory domains of 4-1BB, OX40, and CD28 are most widely used in engineering chimeric antigen receptor T-cells to augment T-cell responses.</p><p><strong>Methods: </strong>In this study, we designed three co-stimulatory trispecific T cell-engaging antibodies (TriTCEs) that target Prostate-specific membrane antigen, CD3, and an additional co-stimulatory receptor(OX40, 4-1BB, or CD28). We conducted comparative profiling of the attributes of distinct co-stimulatory signals to T-cell functions in prostate cancer models.</p><p><strong>Results: </strong>Co-stimulatory trispecific T-cell engagers enhance T-cell activation, proliferation, and display tumor cell-killing activity in vitro. These trispecific antibodies further boosted antitumor activity in humanized mouse xenograft models and increased the infiltration of CD45⁺ immune cells into solid tumors. Specifically, TriTCE-4-1BB and TriTCE-CD28 selectively promoted the expansion of effector memory T cells and increased the presence of CD4⁺ T cells more than TriTCE-OX40. T cells stimulated with TriTCE-4-1BB exhibited reduced exhaustion. Furthermore, T cells treated with co-stimulatory trispecific antibodies demonstrated enhanced metabolic activity characterized by increased oxidative phosphorylation and elevated glycolysis.</p><p><strong>Conclusions: </strong>Collectively, incorporating co-stimulatory receptor targeting domains represents a potentially effective strategy to unlock the full therapeutic potential of T-cell-engaging antibodies for the treatment of solid tumors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>BTLA</i> promoter hypomethylation correlates with enhanced immune cell infiltration, favorable prognosis, and immunotherapy response in melanoma.","authors":"Minglei Yang, Chenxi Zheng, Yu Miao, Cuicui Yin, Longfei Tang, Chongli Zhang, Pu Yu, Qingfang Han, Yihui Ma, Shenglei Li, Guozhong Jiang, Wencai Li, Peiyi Xia","doi":"10.1136/jitc-2024-009841","DOIUrl":"https://doi.org/10.1136/jitc-2024-009841","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint blockade (ICB)-based immunotherapy has significantly improved survival in advanced melanoma. However, many patients exhibit resistance to these therapies. This study examines the impact of <i>BTLA</i> promoter methylation on its expression, immune cell infiltration, and clinical outcomes, evaluating its potential as a prognostic and predictive biomarker for immunotherapy response.</p><p><strong>Methods: </strong>We analyzed methylation and gene expression data from public datasets (The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO)) and an in-house cohort of melanoma patients treated with ICB therapy at the First Affiliated Hospital of Zhengzhou University. We developed a quantitative methylation-specific PCR (qMSP) assay to measure methylation levels of the cg24157392 and cg03995631 CpG sites, and a targeted bisulfite sequencing assay was used to validate the accuracy of qMSP. We measured BTLA protein expression using multiplex immunofluorescence and immunohistochemical staining methods. Pearson correlation, survival analysis, and immune cell infiltration estimation were conducted to explore the associations between <i>BTLA</i> promoter methylation, mRNA and protein expression, clinical outcomes, and immune characteristics.</p><p><strong>Results: </strong>Hypomethylation at CpG sites cg24157392 and cg03995631 in the <i>BTLA</i> promoter were significantly associated with higher <i>BTLA</i> mRNA and protein expression. In the TCGA dataset, low methylation at these sites predicted longer overall survival and was validated in an independent cohort of 50 stage III/IV melanoma patients, with an area under the curve of 0.94 for predicting 5-year survival. Furthermore, <i>BTLA</i> promoter hypomethylation correlated with higher infiltration of immune cells, such as CD8+T cells, CD4+T cells, B cells, and macrophages. Additionally, low methylation at cg24157392 and cg03995631, as quantified by the qMSP assay, was significantly associated with better progression-free survival in patients treated with immune checkpoint inhibitors. These findings were further validated using GEO datasets.</p><p><strong>Conclusions: </strong><i>BTLA</i> promoter hypomethylation serves as a significant biomarker for favorable prognosis and enhanced response to ICB therapy in melanoma. The developed qMSP assays for cg24157392 and cg03995631 accurately quantified methylation levels and demonstrated their potential for clinical application in patient stratification and personalized immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell spatial transcriptomics unravels cell states and ecosystems associated with clinical response to immunotherapy.","authors":"Ziena Abdulrahman, Roderick C Slieker, Daniel McGuire, Marij J P Welters, Mariette I E van Poelgeest, Sjoerd H van der Burg","doi":"10.1136/jitc-2024-011308","DOIUrl":"https://doi.org/10.1136/jitc-2024-011308","url":null,"abstract":"<p><strong>Background: </strong>The tumor microenvironment (TME) is a complex and dynamic ecosystem that is known to influence responses to immunotherapy. We leveraged single-cell spatial transcriptomics to systematically dissect the intricate complexity of the TME, in particular the cellular heterogeneity and spatial interactions. Their collective impact on immunotherapy efficacy was studied in the context of a homogeneous group of patients with vulvar high-grade squamous intraepithelial lesions (vHSIL) treated with an immunotherapeutic tumor-specific peptide vaccine.</p><p><strong>Methods: </strong>We performed single-cell spatial transcriptomics on 20 pretreatment vHSIL lesions, stratified by clinical response to immunotherapeutic vaccination into complete responders (CR), partial responders (PR) and non-responders (NR). Using a 1,000-gene panel, we mapped over 274,000 single cells in situ, identifying 18 cell clusters and 99 distinct non-epithelial cell states. Findings were validated against public single-cell transcriptomic data sets to assess their broader relevance across tumor types.</p><p><strong>Results: </strong>Profound heterogeneity within the TME was detected across the response groups. CR lesions exhibited a higher ratio of immune-supportive to immune-suppressive cells-a pattern mirrored in other solid tumors following neoadjuvant checkpoint blockade. Key immune populations enriched in CRs included CD4+CD161+ effector T cells and chemotactic CD4+ and CD8+ T cells. Conversely, PRs were characterized by increased proportions of T helper 2 cells and CCL18-expressing macrophages, which are associated with the recruitment of type 2 T cells and regulatory T cells. NRs displayed preferential infiltration with immunosuppressive fibroblasts. Distinct spatial immune ecosystems further defined response groups. Although a number of immune cells were detected in all patients, type 1 effector cells dominated interactions in CRs, type 2 cells were prominently interacting in PRs, while NRs lacked organized immune cell interactions.</p><p><strong>Conclusions: </strong>This study underscores the dual importance of both cellular composition and spatial organization in steering clinical response to immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myeloid targeting antibodies PY159 and PY314 for platinum-resistant ovarian cancer.","authors":"Oladapo O Yeku, Minal Barve, Winston W Tan, Judy Wang, Amita Patnaik, Patricia LoRusso, Debra L Richardson, Abdul Rafeh Naqash, Sarah K Lynam, Siqing Fu, Michael Gordon, Joleen Hubbard, Shivaani Kummar, Christos Kyriakopoulos, Afshin Dowlati, Marc Chamberlain, Ira Winer","doi":"10.1136/jitc-2024-010959","DOIUrl":"https://doi.org/10.1136/jitc-2024-010959","url":null,"abstract":"<p><strong>Background: </strong>Novel treatment options are required in patients with platinum-resistant ovarian cancer (PROC). Myeloid-derived suppressor cells promote a hostile tumor microenvironment and are associated with worse clinical outcomes in PROC. We evaluated the safety and preliminary efficacy of PY159, an agonist antibody to Triggering receptor expressed on myeloid cells-1 (TREM1) that reprograms immunosuppressive intratumoral myeloid cells, and PY314, an antagonist antibody to Triggering receptor expressed on myeloid cells-2 (TREM2) that depletes tumor-associated macrophages, as single agents and in combination with pembrolizumab in subjects with PROC.</p><p><strong>Methods: </strong>PY159 and PY314 were individually evaluated in patients with PROC. Patients were treated with monotherapy (PY159 3 mg/kg or PY314 10 mg/kg), based on the recommended dose for expansion derived from the phase 1a studies. At the time of first progression, patients could continue study drug and crossover to combination therapy with pembrolizumab (200 mg) every 3 weeks at the discretion of the investigator. Disease assessment by Response Evaluation Criteria in Solid Tumor version 1.1 was performed every 6 weeks.</p><p><strong>Results: </strong>17 patients were enrolled in the PY159 study (median age 67, range 22-77; median prior therapies 6, range 2-18) and 16 patients in PY314 (median age 65.5, range 49-81; median prior therapies 4, range 2-10). 7 patients in PY159 and 8 patients in PY314 crossed over to combination therapy. Safety events included the following: treatment-related adverse events occurred in 15 patients (88.2%) in PY159 and 9 patients (56.3%) in PY314. Infusion-related reactions occurred in 6 patients (35.3%) in PY159 and 3 patients (18.8%) in PY314. Immune-related adverse events occurred in 13 patients (76.5%) in PY159 (arthralgias) and 1 patient (6.3%) in PY314 (diarrhea). Serious adverse events occurred in 6 patients (36.3%) in PY159 (1 related) and 12 patients (75%) in PY314 (all unrelated). The best radiographic response in PY159 was stable disease in 8/16 patients (50%; median 16 weeks, range 9-33), and in PY314, it was stable disease in 8/16 patients (50%; median 12 weeks, range 6-36). Median PFS was 2.76 months and 2.69 months in PY159 and PY314, respectively. There were no responses in the crossover arm.</p><p><strong>Conclusions: </strong>Both PY159 and PY314 were well tolerated, with an acceptable safety profile, as both single agents and in combination with pembrolizumab. Both agents warrant further investigation in heavily pretreated PROC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RANKL blockade inhibits cancer growth through reversing the tolerogenic profile of tumor-infiltrating (plasmacytoid) dendritic cells.","authors":"Charlotte Pilard, Patrick Roncarati, Marie Ancion, Margaux Luyckx, Michael Renard, Celia Reynders, Thomas Lerho, Florian Poulain, Diane Bruyere, Alizee Lebeau, Elodie Hendrick, Rebekah Crake, Raphael Peiffer, Marie-Julie Nokin, Olivier Peulen, Philippe Delvenne, Pascale Hubert, Michael Herfs","doi":"10.1136/jitc-2024-010753","DOIUrl":"https://doi.org/10.1136/jitc-2024-010753","url":null,"abstract":"<p><strong>Background: </strong>Originally identified for its involvement in bone remodeling, accumulating data emerged in the past years indicating that receptor activator of nuclear factor κB ligand (RANKL) actually acts as a multifunctional soluble molecule that influences various physiological and pathological processes. Regarding its role in carcinogenesis, while direct effects on tumor cell behavior have been precisely characterized, the impact of the RANKL/RANK system (and its inhibition) on the intratumoral immune landscape remains unclear.</p><p><strong>Methods: </strong>After various in silico/in situ/in vitro analyses, the immunotherapeutic efficacy of RANKL blockade (alone and in combination with immune checkpoint inhibitors (anti-programmed cell death protein-1 (PD-1)) or doxorubicin/paclitaxel-based chemotherapy) was investigated using different syngeneic mouse models of triple-negative breast cancer (4T1, 67NR and E0771). Isolated from retrieved tumors, 14 immune cell (sub)populations, along with the activation status of antigen-presenting cells, were thoroughly analyzed in each condition. Finally, the impact of RANKL on the functionality of both dendritic cells (DC) and plasmacytoid dendritic cells (pDC) was determined.</p><p><strong>Results: </strong>A drastic tumor growth inhibition was reproductively observed following RANKL inhibition. Strikingly, this antitumor activity was not detected in immunocompromised mice, demonstrating its dependence on the adaptive immune responses and justifying the diverse enriched signatures linked to immune cell regulation/differentiation detected in RANKL^high-expressing human neoplasms. Interestingly, neoadjuvant chemotherapy (but not PD-1 checkpoint inhibition) potentiated the anticancer effects of RANKL blockade by priming effector T cells and increasing their infiltration within the tumor microenvironment. Mechanistically, we highlighted that RANKL indirectly promotes regulatory T cell differentiation and suppressive function by inhibiting the mTOR signaling pathway on antigen-presenting cells.</p><p><strong>Conclusions: </strong>Taken together, this study provides insight into the role of RANKL/RANK axis in immune tolerance, demonstrates the significant impact of RANKL-dependent impairment of T cell-DC/pDC crosstalk on tumor development and, ultimately, supports that this ligand could be an interesting actionable target for cancer immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel anti-CD73-IL-2v bispecific fusion protein augments antitumor immunity by alleviating immunosuppressive adenosine pathways in CD8⁺ T cells.","authors":"Kayoung Shin, Min Park, Seoho Kim, Haejong Lee, Yuseong Lee, Jongil Kim, Suyoun Park, Jisoo Kim, Kyungwha Lee, Chong Woo Park, Ji-Hyun Kim, Eun-Jin Lee, Hyuckjun Mok, Sung-Man Oh, Sanghee Lee, Young Min Oh, Wonjae Lee, Yaein Amy Shim, Young-Gyu Cho, Junsik Park, Jung-Yun Lee, Young Jun Koh, Kook Hwan Kim, Myoung Ho Jang","doi":"10.1136/jitc-2023-008594","DOIUrl":"https://doi.org/10.1136/jitc-2023-008594","url":null,"abstract":"<p><strong>Background: </strong>Adenosine accumulated in the tumor microenvironment functions as an immune-modulating factor, exerting immunosuppressive actions via adenosine A2A/A2B receptor (A2AR/A2BR) in various immune cell types. CD73, a key enzymatic regulator responsible for adenosine production, is frequently overexpressed in diverse cancers, and its overexpression is associated with reduced responsiveness to conventional anti-cancer drug treatments such as chemotherapy, radiation therapy, targeted therapy, or immunotherapy. Despite numerous therapeutic applications of IL-2 in cancer immunotherapy, the relationship between the CD73-adenosine axis and IL-2-based immunotherapy remains largely unexplored.</p><p><strong>Methods: </strong>To evaluate the effect of CD73 blockade on IL-2 signaling of CD8⁺ T cells, we screened novel CD73 antibodies using human single-chain variable fragment phage library and immunized Alpaca phage library. To optimize targeting to CD73-expressing cells and reinvigorate the antitumor effect of IL-2 in adenosine-rich microenvironment, we engineered a novel bifunctional GI-αCD73/IL-2v fusion protein. Functionality of GI-αCD73/IL-2v fusion protein was assessed in the in vitro cell-based assays and the in vivo tumor-bearing mouse model or cynomolgus monkey.</p><p><strong>Results: </strong>IL-2-induced increase in proliferation of CD8⁺ T cells was not observed under adenosine-rich microenvironment. We demonstrated that the functional impairment of IL-2 signaling in CD8⁺ T cells in these conditions can be reversed by our anti-CD73 antibody (GI-αCD73). Furthermore, GI-αCD73/IL-2v fusion protein significantly restored the impaired proliferation of CD8⁺ T cells and consequently enhanced tumor cell killing under adenosine-mediated immunosuppression, surpassing the combined treatment of GI-αCD73 and Fc-IL-2v. These synergistic effects were attributed to the enhanced delivery of the IL-2v component of GI-αCD73/IL-2v to IL-2Rβγ on CD73-expressing CD8⁺ T cells through a cis-binding mechanism. GI-αCD73/IL-2v elicited a potent antitumor effect in both the human CD73 knock-in (hCD73 KI) mouse model and the humanized mouse model. In non-human primates, GI-αCD73/IL-2v exhibited excellent tolerability while inducing robust and durable expansions of cytotoxic lymphocytes.</p><p><strong>Conclusions: </strong>GI-αCD73/IL-2v bispecific protein is a novel and potent immunocytokine with significant antitumor immunity through cis-binding on CD8⁺ T cells.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fc-mediated immune stimulating, pro-inflammatory and antitumor effects of anti-HER2 IgE against HER2-expressing and trastuzumab-resistant tumors.","authors":"Melanie Grandits, Lais C G F Palhares, Gabriel Osborn, Jitesh Chauhan, Katie Stoker, Heng Sheng Sow, Rebecca Adams, Alex J McCraw, Alicia Chenoweth, Sofia Vlasova, Jacobo López-Abente, Kristina M Ilieva, James Birtley, Sophia Tsoka, Elizabeth Hardaker, Kevin FitzGerald, Sophia N Karagiannis, Heather J Bax","doi":"10.1136/jitc-2024-010945","DOIUrl":"https://doi.org/10.1136/jitc-2024-010945","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Anti-human epidermal growth factor receptor 2 (HER2) IgG1-based antibody therapies significantly improve cancer prognosis, yet intrinsic or acquired resistance to fragment antigen-binding (Fab)-mediated direct effects commonly occurs. Most resistant tumors retain antigen expression and therefore remain potentially targetable with anti-HER2 therapies that promote immune-mediated responses. Tumor-antigen-specific IgE class antibodies can mediate powerful immune cell-mediated effects against different cancers and have been shown to activate IgE Fc receptor-expressing monocytes. We previously reported the engineering of a trastuzumab-equivalent anti-HER2 IgE antibody and showed early evidence of Fc-mediated cancer cell-targeting effects. In the present study, we evaluated the anti-tumoral functions of two anti-HER2 IgEs, trastuzumab and pertuzumab IgE.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In vitro functionality of the two anti-HER2 antibodies was assessed by HER2 phosphorylation and ligand-independent viability assays, as well as basophil (RBL-SX38) degranulation, antibody-dependent cellular cytotoxicity/antibody-dependent cellular phagocytosis(ADCC/ADCP) assays and primary monocyte stimulation assays. The potential to trigger a hypersensitivity type I reaction was investigated using the basophil activation test (BAT). anti-tumoral efficacy was assessed in two humanized HER2+, trastuzumab-resistant models in vivo. Changes in the tumor microenvironment were assessed by flow cytometry or bulk RNA sequencing.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We demonstrate the anti-tumoral and immunostimulatory functions of two anti-HER2 IgEs derived from variable region sequences of the clinically available trastuzumab and pertuzumab IgG1 antibodies. IgE engagement of monocytes via the Fc region induced tumor cell cytotoxicity and a pro-inflammatory shift with upregulation of immune-stimulatory CD40, CD80 and CD86, and downregulation of scavenger CD163, cell surface molecules. This was accompanied by enhanced pro-inflammatory tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β cytokine production. The absence of basophil activation by anti-HER2 IgEs ex vivo in whole blood points to potentially safe administration in humans. In two trastuzumab-resistant HER2+ tumor xenograft models in immunodeficient mice reconstituted with human immune cells, the trastuzumab-equivalent anti-HER2 IgE restricted tumor growth. Treatment was associated with enriched classical (CD14&lt;sup&gt;+&lt;/sup&gt;CD16&lt;sup&gt;-&lt;/sup&gt;) monocyte and lower alternatively-activated (CD163&lt;sup&gt;+&lt;/sup&gt;CD206&lt;sup&gt;+&lt;/sup&gt;) macrophage infiltration, and higher densities of activated CD4&lt;sup&gt;+&lt;/sup&gt; (CD127&lt;sup&gt;lo&lt;/sup&gt;CD25&lt;sup&gt;hi&lt;/sup&gt;) T cells and favorable effector T cell(Teff) to regulatory T cell (Treg) ratios in tumors.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Collectively, anti-HER2 IgE maintains Fab-mediated antitumor activity, induces Fc-mediated effects against HER2-expressing tumor cells, and","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}