Oncoimmunology最新文献

{"title":"Elimination of cDC1 cells by regulatory T cells jeopardizes cancer immunotherapy.","authors":"Peng Liu, Liwei Zhao, Guido Kroemer, Oliver Kepp","doi":"10.1080/2162402X.2024.2412874","DOIUrl":"10.1080/2162402X.2024.2412874","url":null,"abstract":"<p><p>Recent findings revealed that neoantigen-specific cytotoxic type 1 regulatory T (T_R1) CD4 T cells can subvert cancer immunotherapy by killing type 1 conventional dendritic cells (cDC1s) that present tumor antigens bound to MHC class II. This underlines the importance of cDC1s for eliciting anticancer immunity but poses a novel clinical challenge.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2412874"},"PeriodicalIF":6.5,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11457612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394377","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":"Peptide-guided adaptor-CAR T-Cell therapy for the treatment of SSTR2-expressing neuroendocrine tumors.","authors":"Christian Pellegrino, Nicholas Favalli, Laura Volta, Ramon Benz, Sara Puglioli, Gabriele Bassi, Kathrin Zitzmann, Christoph Josef Auernhammer, Svenja Nölting, Chiara F Magnani, Dario Neri, Felix Beuschlein, Markus G Manz","doi":"10.1080/2162402X.2024.2412371","DOIUrl":"https://doi.org/10.1080/2162402X.2024.2412371","url":null,"abstract":"<p><p>Somatostatin receptor type 2 (SSTR2) is one of the five subtypes of somatostatin receptors and is overexpressed on the surface of most gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs), pituitary tumors, paraganglioma, and meningioma, as well as hepatocellular carcinoma and breast cancer. Chimeric antigen receptor (CAR) T-cells are genetically engineered to express an artificial, T-cell activating binder, leading upon ligation to biocidal activity against target-antigen expressing cells. Adaptor-CAR T-cells recognize, via the CAR, a tag on an antigen-binding molecule, building an activating bridge between the CAR and the target cell. We hypothesized that a novel fluorescent-peptide antagonist of SSTR2, called Octo-Fluo, in combination with anti-FITC adaptor CAR (AdFITC(E2)-CAR) T-cells, may function as an on-off tunable activating bridge between the CAR and SSTR2 expressing target cells. In vitro studies confirmed the binding of Octo-Fluo to Bon1-SSTR2 mCherry-Luc cells without evidence of internalization. AdFITC(E2)-CAR T-cells were activated and efficiently induced Bon1-SSTR2 cell death in vitro, in an Octo-Fluo concentration-dependent manner. Similarly, AdFITC(E2)-CAR T-cells in combination with Octo-Fluo efficiently infiltrated the tumor and eliminated Bon1-SSTR2 tumors in immunodeficient mice in therapeutic settings. Both, AdFITC(E2)-CAR T-cell tumor infiltration and biocidal activity were Octo-Fluo concentration-dependent, with high doses of Octo-Fluo, saturating both the CAR and the SSTR2 antigen independently, leading to the loss of tumor infiltration and biocidal activity due to the loss of bridge formation. Our findings demonstrate the potential of using AdFITC(E2)-CAR T-cells with Octo-Fluo as a versatile, on-off tunable bispecific adaptor for targeted CAR T-cell immunotherapy against SSTR2-positive NETs.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2412371"},"PeriodicalIF":6.5,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11457607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394378","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":"High-grade serous ovarian cancer development and anti-PD-1 resistance is driven by IRE1α activity in neutrophils.","authors":"Alexander Emmanuelli, Camilla Salvagno, Sung-Min Hwang, Deepika Awasthi, Tito A Sandoval, Chang-Suk Chae, Jin-Gyu Cheong, Chen Tan, Takao Iwawaki, Juan R Cubillos-Ruiz","doi":"10.1080/2162402X.2024.2411070","DOIUrl":"10.1080/2162402X.2024.2411070","url":null,"abstract":"<p><p>High-grade serious ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here, we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1α. We found that intratumoral neutrophils exhibited overactivation of ER stress response markers compared with their counterparts at non-tumor sites. Selective deletion of IRE1α in neutrophils delayed primary ovarian tumor growth and extended the survival of mice with HGSOC by enabling early T cell-mediated tumor control. Notably, loss of IRE1α in neutrophils sensitized tumor-bearing mice to PD-1 blockade, inducing HGSOC regression and long-term survival in ~ 50% of the treated hosts. Hence, neutrophil-intrinsic IRE1α facilitates early adaptive immune escape in HGSOC and targeting this ER stress sensor might be used to unleash endogenous and immunotherapy-elicited immunity that controls metastatic disease.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2411070"},"PeriodicalIF":6.5,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11448341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical prognosticators and targets in the immune microenvironment of intrahepatic cholangiocarcinoma.","authors":"Isis Lozzi, Alexander Arnold, Matthias Barone, Juliette Claire Johnson, Bruno V Sinn, Johannes Eschrich, Pimrapat Gebert, Ruonan Wang, Mengwen Hu, Linda Feldbrügge, Anja Schirmeier, Anja Reutzel-Selke, Thomas Malinka, Felix Krenzien, Wenzel Schöning, Dominik P Modest, Johann Pratschke, Igor M Sauer, Matthäus Felsenstein","doi":"10.1080/2162402X.2024.2406052","DOIUrl":"10.1080/2162402X.2024.2406052","url":null,"abstract":"<p><strong>Background: </strong>Intrahepatic cholangiocarcinoma (ICC) is a disease with poor prognosis and limited therapeutic options. We investigated the tumor immune microenvironment (TIME) to identify predictors of disease outcome and to explore targets for therapeutic modulation.</p><p><strong>Methods: </strong>Liver tissue samples were collected during 2008-2019 from patients (<i>n</i> = 139) diagnosed with ICC who underwent curative intent surgery without neoadjuvant chemotherapy. Samples from the discovery cohort (<i>n</i> = 86) were immunohistochemically analyzed on tissue microarrays (TMAs) for the expression of CD68, CD3, CD4, CD8, Foxp3, PD-L1, STAT1, and p-STAT1 in tumor core and stroma areas. Results were digitally analyzed using QuPath software and correlated with clinicopathological characteristics. For validation of TIME-related biomarkers, we performed multiplex imaging mass cytometry (IMC) in a validation cohort (<i>n</i> = 53).</p><p><strong>Results: </strong>CD68+ cells were the predominant immune cell type in the TIME of ICC. CD4+^high T cell density correlated with better overall survival (OS). Prediction modeling together with validation cohort confirmed relevance of CD4+ cells, PD-L1 expression by immune cells in the stroma and N-stage on overall disease outcome. In turn, IMC analyses revealed that silent CD3+CD4+ clusters inversely impacted survival. Among annotated immune cell clusters, PD-L1 was most relevantly expressed by CD4+FoxP3+ cells. A subset of tumors with high density of immune cells (\"hot\" cluster) correlated with PD-L1 expression and could identify a group of candidates for immune checkpoint inhibition (ICI). Ultimately, higher levels of STAT1 expression were associated with higher lymphocyte infiltration and PD-L1 expression.</p><p><strong>Conclusions: </strong>These results highlight the importance of CD4+ T cells in immune response against ICC. Secondly, a subset of tumors with \"hot\" TIME represents potential candidates for ICI, while stimulation of STAT1 pathway could be a potential target to turn \"cold\" into \"hot\" TIME in ICC.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2406052"},"PeriodicalIF":6.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367086","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":"Enhancing T-cell recruitment in renal cell carcinoma with cytokine-armed adenoviruses.","authors":"Michaela Feodoroff, Firas Hamdan, Gabriella Antignani, Sara Feola, Manlio Fusciello, Salvatore Russo, Jacopo Chiaro, Katja Välimäki, Teijo Pellinen, Rui M Branca, Janne Lehtiö, Federica D Alessio, Paolo Bottega, Virpi Stigzelius, Janita Sandberg, Jonna Clancy, Jukka Partanen, Minna Malmstedt, Antti Rannikko, Vilja Pietiäinen, Mikaela Grönholm, Vincenzo Cerullo","doi":"10.1080/2162402X.2024.2407532","DOIUrl":"10.1080/2162402X.2024.2407532","url":null,"abstract":"<p><p>Immunotherapy has emerged as a promising approach for cancer treatment, with oncolytic adenoviruses showing power as immunotherapeutic agents. In this study, we investigated the immunotherapeutic potential of an adenovirus construct expressing CXCL9, CXCL10, or IL-15 in clear cell renal cell carcinoma (ccRCC) tumor models. Our results demonstrated robust cytokine secretion upon viral treatment, suggesting effective transgene expression. Subsequent analysis using resistance-based transwell migration and microfluidic chip assays demonstrated increased T-cell migration in response to chemokine secretion by infected cells in both 2D and 3D cell models. Flow cytometry analysis revealed CXCR3 receptor expression across T-cell subsets, with the highest percentage found on CD8+ T-cells, underscoring their key role in immune cell migration. Alongside T-cells, we also detected NK-cells in the tumors of immunocompromised mice treated with cytokine-encoding adenoviruses. Furthermore, we identified potential immunogenic antigens that may enhance the efficacy and specificity of our armed oncolytic adenoviruses in ccRCC. Overall, our findings using ccRCC cell line, <i>in vivo</i> humanized mice, physiologically relevant PDCs in 2D and patient-derived organoids (PDOs) in 3D suggest that chemokine-armed adenoviruses hold promise for enhancing T-cell migration and improving immunotherapy outcomes in ccRCC. Our study contributes to the development of more effective ccRCC treatment strategies by elucidating immune cell infiltration and activation mechanisms within the tumor microenvironment (TME) and highlights the usefulness of PDOs for predicting clinical relevance and validating novel immunotherapeutic approaches. Overall, our research offers insights into the rational design and optimization of viral-based immunotherapies for ccRCC.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2407532"},"PeriodicalIF":6.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11441019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142356459","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":"Immune priming and induction of tertiary lymphoid structures in a cord-blood humanized mouse model of gastrointestinal stromal tumor.","authors":"Bo He, Larissa Dymond, Kira H Wood, Edward R Bastow, Jiulia Satiaputra, Ji Li, Anna Johansson-Percival, Juliana Hamzah, M Priyanthi Kumarasinghe, Mohammed Ballal, Jonathan Foo, Mikael Johansson, Hooi C Ee, Scott W White, Louise Winteringham, Ruth Ganss","doi":"10.1080/2162402X.2024.2406576","DOIUrl":"10.1080/2162402X.2024.2406576","url":null,"abstract":"<p><p>Gastrointestinal stromal tumors (GISTs) harbor diverse immune cell populations but so far immunotherapy in patients has been disappointing. Here, we established cord blood humanized mouse models of localized and disseminated GIST to explore the remodeling of the tumor environment for improved immunotherapy. Specifically, we assessed the ability of a cancer vascular targeting peptide (VTP) to bind to mouse and patient GIST angiogenic blood vessels and deliver the TNF superfamily member LIGHT (TNFS14) into tumors. LIGHT-VTP treatment of GIST in humanized mice improved vascular function and tumor oxygenation, which correlated with an overall increase in intratumoral human effector T cells. Concomitant with LIGHT-mediated vascular remodeling, we observed intratumoral high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), which resemble spontaneous TLS found in GIST patients. Thus, by overcoming the limitations of immunodeficient xenograft models, we demonstrate the therapeutic feasibility of vascular targeting and immune priming in human GIST. Since TLS positively correlate with patient prognosis and improved response to immune checkpoint inhibition, vascular LIGHT targeting in GIST is a highly translatable approach to improve immunotherapeutic outcomes.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2406576"},"PeriodicalIF":6.5,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308843","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":"CD4⁺ tumor-infiltrating lymphocytes secreting T cell-engagers induce regression of autologous patient-derived non-small cell lung cancer xenografts.","authors":"Anaïs Jiménez-Reinoso, Magdalena Molero-Abraham, Cristina Cirauqui, Belén Blanco, Eva M Garrido-Martin, Daniel Nehme-Álvarez, Carmen Domínguez-Alonso, Ángel Ramírez-Fernández, Laura Díez-Alonso, Ángel Nuñez-Buiza, África González-Murillo, Raquel Tobes, Eduardo Pareja, Manuel Ramírez-Orellana, José Luis Rodriguez-Peralto, Irene Ferrer, Jon Zugazagoitia, Luis Paz-Ares, Luis Álvarez-Vallina","doi":"10.1080/2162402X.2024.2392897","DOIUrl":"10.1080/2162402X.2024.2392897","url":null,"abstract":"<p><p>Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown remarkable results in melanoma, but only modest clinical benefits in other cancers, even after TIL have been genetically modified to improve their tumor homing, cytotoxic potential or overcome cell exhaustion. The required <i>ex vivo</i> TIL expansion process may induce changes in the T cell clonal composition, which could likely compromise the tumor reactivity of TIL preparations and ultimately the success of TIL therapy. A promising approach based on the production of bispecific T cell-engagers (TCE) by engineered T cells (STAb-T therapy) improves the efficacy of current T cell redirection strategies against tumor-associated antigens in hematological tumors. We studied the TCRβ repertoire in non-small cell lung cancer (NSCLC) tumors and in <i>ex vivo</i> expanded TIL from two unrelated patients. We generated TIL secreting anti-epidermal growth factor receptor (EGFR) × anti-CD3 TCE (TIL^STAb) and tested their antitumor efficacy <i>in vitro</i> and <i>in vivo</i> using a NSCLC patient-derived xenograft (PDX) model in which tumor fragments and TIL from the same patient were transplanted into <i>hIL-2</i> NOG mice. We confirmed that the standard TIL expansion protocol promotes the loss of tumor-dominant T cell clones and the overgrowth of virus-reactive TCR clonotypes that were marginally detectable in primary tumors. We demonstrated the antitumor activity of TIL^STAb both <i>in vitro</i> and <i>in vivo</i> when administered intratumorally and systemically in an autologous immune-humanized PDX EGFR⁺ NSCLC mouse model, where tumor regression was mediated by TCE-redirected CD4⁺ TIL bearing non-tumor dominant clonotypes.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2392897"},"PeriodicalIF":6.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11352715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142113732","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":"Metabolic regulation of the mitochondrial immune checkpoint.","authors":"David C Montrose, Suchandrima Saha, Lorenzo Galluzzi","doi":"10.1080/2162402X.2024.2394247","DOIUrl":"10.1080/2162402X.2024.2394247","url":null,"abstract":"<p><p>Disrupting mitochondrial function in malignant cells is a promising strategy to enhance anticancer immunity. We have recently demonstrated that depriving colorectal cancer cells of serine results in mitochondrial dysfunction coupled with the cytosolic accumulation of mitochondrial DNA and consequent activation of CGAS- and STING-dependent tumor-targeting immune responses.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2394247"},"PeriodicalIF":6.5,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11352702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142113733","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":"Overexpression of CCL-20 and CXCL-8 genes enhances tumor escape and resistance to cemiplimab, a programmed cell death protein-1 (PD-1) inhibitor, in patients with locally advanced and metastatic cutaneous squamous cell carcinoma.","authors":"Vincenzo De Falco, Stefania Napolitano, Renato Franco, Federica Zito Marino, Luigi Formisano, Daniela Esposito, Gabriella Suarato, Rossella Napolitano, Alfonso Esposito, Francesco Caraglia, Maria Cristina Giugliano, Eleonora Cioli, Vincenzo Famiglietti, Roberto Bianco, Giuseppe Argenziano, Andrea Ronchi, Davide Ciardiello, Valerio Nardone, Emma D'Ippolito, Sara Del Tufo, Fortunato Ciardiello, Teresa Troiani","doi":"10.1080/2162402X.2024.2388315","DOIUrl":"10.1080/2162402X.2024.2388315","url":null,"abstract":"<p><p>Cemiplimab has demonstrated relevant clinical activity in cutaneous squamous cell carcinoma (cSCC) but mechanisms of primary and acquired resistance to immunotherapy are still unknown. We collected clinical data from locally advanced and/or metastatic cSSC patients treated with cemiplimab in two Italian University centers. In addition, gene expression analysis by using Nanostring Technologies platform to evaluate 770 cancer- and immune-related genes on 20 tumor tissue samples (9 responders and 11 non-responders to cemiplimab) was performed. We enrolled 81 patients with a median age of 82 years. After 16.4 months of median follow-up, 12- and 24-months PFS were 53% and 42%, respectively; while 12- and 24-months OS were 71% and 61%, respectively. Treatment was well tolerated. Overall response rate (ORR) was 58%, with a disease control rate (DCR) of 77.8%. The difference between genes expressed in responder versus non-responder patient samples was substantial, particularly for genes involved in immune system regulation. Cemiplimab-resistant tumors were associated with over-expression of CCL-20 and CXCL-8. Cemiplimab confirmed efficacy and safety data in real-life cSCC patients. Overexpression of CCL-20 and CXCL-8 could represent biomarkers of lack of response to immunotherapy.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2388315"},"PeriodicalIF":6.5,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11352706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142113734","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":"Local therapy with combination TLR agonists stimulates systemic anti-tumor immunity and sensitizes tumors to immune checkpoint blockade.","authors":"Francois Xavier Rwandamuriye, Tao Wang, Hanfu Zhang, Omar Elaskalani, Jorren Kuster, Xueting Ye, Breana Vitali, Juliët Schreurs, M Lizeth Orozco Morales, Marck Norret, Cameron W Evans, Rachael M Zemek, K Swaminathan Iyer, W Joost Lesterhuis, Ben Wylie","doi":"10.1080/2162402X.2024.2395067","DOIUrl":"10.1080/2162402X.2024.2395067","url":null,"abstract":"<p><p>Toll-like receptor (TLR) agonists are being developed as anti-cancer therapeutics due to their potent immunostimulatory properties. However, clinical trials testing TLR agonists as monotherapy have often failed to demonstrate significant improvement over standard of care. We hypothesized that the anti-cancer efficacy of TLR agonist immunotherapy could be improved by combinatorial approaches. To prevent increased toxicity, often seen with systemic combination therapies, we developed a hydrogel to deliver TLR agonist combinations at low doses, locally, during cancer debulking surgery. Using tumor models of WEHI 164 and bilateral M3-9-M sarcoma and CT26 colon carcinoma, we assessed the efficacy of pairwise combinations of poly(I:C), R848, and CpG in controlling local and distant tumor growth. We show that combination of the TLR3 agonist poly(I:C) and TLR7/8 agonist R848 drives anti-tumor immunity against local and distant tumors. In addition, combination of local poly(I:C) and R848 sensitized tumors to systemic immune checkpoint blockade, improving tumor control. Mechanistically, we demonstrate that local therapy with poly(I:C) and R848 recruits inflammatory monocytes to the tumor draining lymph nodes early in the anti-tumor response. Finally, we provide proof of concept for intraoperative delivery of poly(I:C) and R848 together via a surgically applicable biodegradable hydrogel.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2395067"},"PeriodicalIF":6.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074255","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}