Oncoimmunology最新文献

{"title":"Decreased melanoma CSF-1 secretion by Cannabigerol treatment reprograms regulatory myeloid cells and reduces tumor progression.","authors":"Iris Wyrobnik, Miryam Steinberg, Anat Gelfand, Ronen Rosenblum, Yara Eid Mutlak, Liron Sulimani, Shiri Procaccia, Yishai Ofran, Hila Novak-Kotzer, David Meiri","doi":"10.1080/2162402X.2023.2219164","DOIUrl":"10.1080/2162402X.2023.2219164","url":null,"abstract":"<p><p>During solid tumor progression, the tumor microenvironment (TME) evolves into a highly immunosuppressive milieu. Key players in the immunosuppressive environment are regulatory myeloid cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), which are recruited and activated via tumor-secreted cytokines such as colony-stimulating factor 1 (CSF-1). Therefore, the depletion of tumor-secreted cytokines is a leading anticancer strategy. Here, we found that CSF-1 secretion by melanoma cells is decreased following treatment with Cannabis extracts. Cannabigerol (CBG) was identified as the bioactive cannabinoid responsible for the effects. Conditioned media from cells treated with pure CBG or the high-CBG extract reduced the expansion and macrophage transition of the monocytic-MDSC subpopulation. Treated MO-MDSCs also expressed lower levels of iNOS, leading to restored CD8+ T-cell activation. Tumor-bearing mice treated with CBG presented reduced tumor progression, lower TAM frequencies and reduced TAM/M1 ratio. A combination of CBG and αPD-L1 was more effective in reducing tumor progression, enhancing survival and increasing the infiltration of activated cytotoxic T-cells than each treatment separately. We show a novel mechanism for CBG in modulating the TME and enhancing immune checkpoint blockade therapy, underlining its promising therapeutic potential for the treatment of a variety of tumors with elevated CSF-1 expression.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2219164"},"PeriodicalIF":7.2,"publicationDate":"2023-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/62/1a/KONI_12_2219164.PMC10262794.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10563976","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":"MicroRNA analysis of Natural Killer cell-derived exosomes: the microRNA let-7b-5p is enriched in exosomes and participates in their anti-tumor effects against pancreatic cancer cells.","authors":"Anna Laura Di Pace, Andrea Pelosi, Piera Filomena Fiore, Nicola Tumino, Francesca Besi, Linda Quatrini, Silvia Santopolo, Paola Vacca, Lorenzo Moretta","doi":"10.1080/2162402X.2023.2221081","DOIUrl":"10.1080/2162402X.2023.2221081","url":null,"abstract":"<p><p>Natural Killer (NK) cells are important components of the immune system in the defense against tumor growth and metastasis. They release exosomes containing proteins and nucleic acids, including microRNAs (miRNAs). NK-derived exosomes play a role in the anti-tumor NK cell function since they are able to recognize and kill cancer cells. However, the involvement of exosomal miRNAs in the function of NK exosomes is poorly understood. In this study, we explored the miRNA content of NK exosomes by microarray as compared to their cellular counterparts. The expression of selected miRNAs and lytic potential of NK exosomes against childhood B acute lymphoblastic leukemia cells after co-cultures with pancreatic cancer cells were also evaluated. We identified a small subset of miRNAs, including miR-16-5p, miR-342-3p, miR-24-3p, miR-92a-3p and let-7b-5p that is highly expressed in NK exosomes. Moreover, we provide evidence that NK exosomes efficiently increase let-7b-5p expression in pancreatic cancer cells and induce inhibition of cell proliferation by targeting the cell cycle regulator CDK6. Let-7b-5p transfer by NK exosomes could represent a novel mechanism by which NK cells counteract tumor growth. However, both cytolytic activity and miRNA content of NK exosomes were reduced upon co-culture with pancreatic cancer cells. Alteration in the miRNA cargo of NK exosomes, together with their reduced cytotoxic activity, could represent another strategy exerted by cancer to evade the immune response. Our study provides new information on the molecular mechanisms used by NK exosomes to exert anti-tumor-activity and offers new clues to integrate cancer treatments with NK exosomes.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2221081"},"PeriodicalIF":7.2,"publicationDate":"2023-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ef/23/KONI_12_2221081.PMC10251800.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10191420","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":"Trial watch: immunotherapeutic strategies on the horizon for hepatocellular carcinoma.","authors":"Benjamin Koh, Darren Jun Hao Tan, Wen Hui Lim, Jeffrey S L Wong, Cheng Han Ng, Kai En Chan, Meng Wang, Wei Peng Yong, Yock Young Dan, Louis Z Wang, Nigel Tan, Mark Muthiah, Alfred Kow, Nicholas L Syn, Daniel Q Huang, Thomas Yau","doi":"10.1080/2162402X.2023.2214478","DOIUrl":"10.1080/2162402X.2023.2214478","url":null,"abstract":"<p><p>The use of immune checkpoint inhibitors (ICIs) targeting PD-L1/PD-1 and CTLA-4 has transformed the oncology practice of hepatocellular carcinoma. However, only 25-30% of the patients with advanced HCC treated with atezolizumab-bevacizumab or tremelimumab-durvalumab (STRIDE) respond initially, and mechanistic biomarkers and novel treatment strategies are urgently needed for patients who present with or acquire resistance to first-line ICI-based therapies. The recent approval of the STRIDE regimen has also engendered new questions, such as patient selection factors (e.g. portal hypertension and history of variceal bleed) and biomarkers, and the optimal combination and sequencing of ICI-based regimens. Triumphs in the setting of advanced HCC have also galvanized considerable interest in the broader application of ICIs to early- and intermediate-stage diseases, including clinical combination of ICIs with locoregional therapies. Among these clinical contexts, the role of ICIs in liver transplantation - which is a potentially curative strategy unique to HCC management - as a bridge to liver transplant in potential candidates or in the setting of post-transplant recurrence, warrants investigation in view of the notable theoretical risk of allograft rejection. In this review, we summarize and chart the landscape of seminal immuno-oncology trials in HCC and envision future clinical developments.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2214478"},"PeriodicalIF":7.2,"publicationDate":"2023-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/19/1b/KONI_12_2214478.PMC10241000.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10191411","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":"Studying TIGIT activity against tumors through the generation of knockout mice.","authors":"Ahmed Rishiq, Reem Bsoul, Ophir Pick, Ofer Mandelboim","doi":"10.1080/2162402X.2023.2217735","DOIUrl":"10.1080/2162402X.2023.2217735","url":null,"abstract":"<p><p>The use of antibodies to block inhibitory receptors, primarily anti-PD1 and CTLA4 (known as checkpoint therapy) revolutionized cancer treatment. However, despite these successes, the majority of cancer patients do not respond to the checkpoint treatment, emphasizing the need for development of additional therapies, which are based on other inhibitory receptors. Human TIGIT is an inhibitory receptor expressed by Natural Killer (NK) and T cells and is mainly known to interact with PVR, Nectin-2, Nectin-3, and Nectin-4. Whether mouse TIGIT interacts with all of these ligands is still unclear. Additionally, the in vivo function of TIGIT against tumors is not completely understood. Here, we demonstrate that mouse TIGIT interacts with and is inhibited by mPVR only. Using CRISPR-Cas9 technology, we generated TIGIT-deficient mice and demonstrated that NK cell cytotoxicity and degranulation against two tumor types were lower in WT mice when compared to the TIGIT KO mice. Moreover, in vivo tumor progression was slower in TIGIT KO than in WT mice. Taken together, our data established that mTIGIT has only one ligand, PVR, and that in the absence of TIGIT tumors are killed better both in vitro and in vivo.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2217735"},"PeriodicalIF":7.2,"publicationDate":"2023-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5f/0b/KONI_12_2217735.PMC10228407.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10194092","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":"IX Forum on Translational Immunology and Cancer Immuno-therapy (FIT Cancer 9)","authors":"W. William, Kwokg","doi":"10.1080/2162402X.2023.2197732","DOIUrl":"https://doi.org/10.1080/2162402X.2023.2197732","url":null,"abstract":"ABSTRACT/INTRODUCTION Tumor immunology and cancer immunotherapy is a growing field, continuously evolving. Different types of immunotherapies have been implemented over last decade in the standard of care across several tumor types. Novel strategies to overcome resistance or to tackle the tumor microenvironment are currently at the forefront of the tumor immunology and cancer immunotherapies research. The Spanish Group for Cancer Immuno-Biotherapies (GÉTICA) held the IX Forum on Translational Immunology and Cancer Immunotherapy (FITCancer 9) from 9-11 March, in Madrid (Spain). FITCancer, which is the largest meeting uniquely focused on cancer immunotherapy, brings together clinicians and researchers, experts in the field of cancer immunology and immunotherapy. Here, we present abstracts submitted by GÉTICA’s members to the IX Forum on Translational Immunology and Cancer Immunotherapy.","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":" ","pages":""},"PeriodicalIF":7.2,"publicationDate":"2023-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46607500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"B cells require licensing by dendritic cells to serve as primary antigen-presenting cells for plasmid DNA.","authors":"Ichwaku Rastogi, Douglas G McNeel","doi":"10.1080/2162402X.2023.2212550","DOIUrl":"10.1080/2162402X.2023.2212550","url":null,"abstract":"<p><p>DNA vaccines have been an attractive approach for treating cancer patients, however have demonstrated modest immunogenicity in human clinical trials. Dendritic cells (DCs) are known to cross-present DNA-encoded antigens expressed in bystander cells. However, we have previously reported that B cells, and not DCs, serve as primary antigen-presenting cells (APCs) following passive uptake of plasmid DNA. Here we sought to understand the requirements for B cells to present DNA-encoded antigens, to ultimately increase the immunogenicity of plasmid DNA vaccines. Using ovalbumin-specific OT-1 CD8+ T cells and isolated APC populations, we demonstrated that following passive uptake of plasmid DNA, B cells but not DC, can translate the encoded antigen. However, CD8 T cells were only activated by B cells when they were co-cultured with DCs. We found that a cell-cell contact is required between B cells and DCs. Using MHCI KO and re-purification studies, we demonstrated that B cells were the primary APCs and DCs serve to license this function. We further identified that the gene expression profiles of B cells that have been licensed by DCs, compared to the B cells that have not, are vastly different and have signatures similar to B cells activated with a TLR7/8 agonist. Our data demonstrate that B cells transcribe and translate antigens encoded by plasmid DNA following passive uptake, however require licensing by live DC to present antigen to CD8 T cells. Further study of the role of B cells as APCs will be important to improve the immunological efficacy of DNA vaccines.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2212550"},"PeriodicalIF":7.2,"publicationDate":"2023-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/08/f9/KONI_12_2212550.PMC10190194.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10563596","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":"A type I interferon footprint in pre-operative biopsies is an independent biomarker that in combination with CD8⁺ T cell quantification can improve the prediction of response to neoadjuvant treatment of rectal adenocarcinoma.","authors":"Azar Rezapour, Daniel Rydbeck, Fabian Byvald, Viktor Tasselius, Gustaf Danielsson, Eva Angenete, Ulf Yrlid","doi":"10.1080/2162402X.2023.2209473","DOIUrl":"10.1080/2162402X.2023.2209473","url":null,"abstract":"<p><p>Tailored treatment for patients with rectal cancer requires clinically available markers to predict their response to neoadjuvant treatment. The quantity of tumor-infiltrating lymphocytes (TILs) in pre-operative tumor biopsies has been suggested to predict a favorable response, but opposing results exist. A biopsy-adapted Immunoscore (IS_B) based on TILs has recently emerged as a promising predictor of tumor regression and prognosis in (colo)rectal cancer. We aimed to refine the IS_B for prediction of response using multiplex immunofluorescence (mIF) on pre-operative rectal cancer biopsies. We combined the distribution and density of conventional T cell subsets and γδT cells with a type I Interferon (IFN)-driven response assessed using Myxovirus resistance protein A (MxA) expression. We found that pathological complete response (pCR) following neoadjuvant treatment was associated with type I IFN. Stratification of patients according to the density of CD8⁺ in the entire tumor tissue and MxA⁺ cells in tumor stroma, where equal weight was assigned to both parameters, resulted in improved predictive quality compared to the IS_B. This novel stratification approach using these two independent parameters in pre-operative biopsies could potentially aid in identifying patients with a good chance of achieving a pCR following neoadjuvant treatment.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2209473"},"PeriodicalIF":7.2,"publicationDate":"2023-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/66/4a/KONI_12_2209473.PMC10173792.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10192346","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":"Increased tryptophan, but not increased glucose metabolism, predict resistance of pembrolizumab in stage III/IV melanoma.","authors":"Jorge D Oldan, Benjamin C Giglio, Eric Smith, Weiling Zhao, Deeanna M Bouchard, Marija Ivanovic, Yueh Z Lee, Frances A Collichio, Michael O Meyers, Diana E Wallack, Amber Abernethy-Leinwand, Patricia K Long, Dimitri G Trembath, Paul B Googe, Madeline H Kowalski, Anastasia Ivanova, Jennifer A Ezzell, Nana Nikolaishvili-Feinberg, Nancy E Thomas, Terence Z Wong, David W Ollila, Zibo Li, Stergios J Moschos","doi":"10.1080/2162402X.2023.2204753","DOIUrl":"10.1080/2162402X.2023.2204753","url":null,"abstract":"<p><p>Clinical trials of combined IDO/PD1 blockade in metastatic melanoma (MM) failed to show additional clinical benefit compared to PD1-alone inhibition. We reasoned that a tryptophan-metabolizing pathway other than the kynurenine one is essential. We immunohistochemically stained tissues along the nevus-to-MM progression pathway for tryptophan-metabolizing enzymes (TMEs; TPH1, TPH2, TDO2, IDO1) and the tryptophan transporter, LAT1. We assessed tryptophan and glucose metabolism by performing baseline C11-labeled α-methyl tryptophan (C11-AMT) and fluorodeoxyglucose (FDG) PET imaging of tumor lesions in a prospective clinical trial of pembrolizumab in MM (clinicaltrials.gov, NCT03089606). We found higher protein expression of all TMEs and LAT1 in melanoma cells than tumor-infiltrating lymphocytes (TILs) within MM tumors (<i>n</i> = 68). Melanoma cell-specific TPH1 and LAT1 expressions were significantly anti-correlated with TIL presence in MM. High melanoma cell-specific LAT1 and low IDO1 expression were associated with worse overall survival (OS) in MM. Exploratory optimal cutpoint survival analysis of pretreatment 'high' vs. 'low' C11-AMT SUV_max of the hottest tumor lesion per patient revealed that the 'low' C11-AMT SUV_max was associated with longer progression-free survival in our clinical trial (<i>n</i> = 26). We saw no such trends with pretreatment FDG PET SUV_max. Treatment of melanoma cell lines with telotristat, a TPH1 inhibitor, increased IDO expression and kynurenine production in addition to suppression of serotonin production. High melanoma tryptophan metabolism is a poor predictor of pembrolizumab response and an adverse prognostic factor. Serotoninergic but not kynurenine pathway activation may be significant. Melanoma cells outcompete adjacent TILs, eventually depriving the latter of an essential amino acid.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2204753"},"PeriodicalIF":7.2,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a0/f0/KONI_12_2204753.PMC10142396.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9752247","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":"Neoadjuvant immune checkpoint blockade triggers persistent and systemic T_reg activation which blunts therapeutic efficacy against metastatic spread of breast tumors.","authors":"Olga S Blomberg, Kevin Kos, Lorenzo Spagnuolo, Olga I Isaeva, Hannah Garner, Max D Wellenstein, Noor Bakker, Danique E M Duits, Kelly Kersten, Sjoerd Klarenbeek, Cheei-Sing Hau, Daphne Kaldenbach, Elisabeth A M Raeven, Kim Vrijland, Marleen Kok, Karin E de Visser","doi":"10.1080/2162402X.2023.2201147","DOIUrl":"10.1080/2162402X.2023.2201147","url":null,"abstract":"<p><p>The clinical successes of immune checkpoint blockade (ICB) in advanced cancer patients have recently spurred the clinical implementation of ICB in the neoadjuvant and perioperative setting. However, how neoadjuvant ICB therapy affects the systemic immune landscape and metastatic spread remains to be established. Tumors promote both local and systemic expansion of regulatory T cells (T_regs), which are key orchestrators of tumor-induced immunosuppression, contributing to immune evasion, tumor progression and metastasis. T_regs express inhibitory immune checkpoint molecules and thus may be unintended targets for ICB therapy counteracting its efficacy. Using ICB-refractory models of spontaneous primary and metastatic breast cancer that recapitulate the poor ICB response of breast cancer patients, we observed that combined anti-PD-1 and anti-CTLA-4 therapy inadvertently promotes proliferation and activation of T_regs in the tumor, tumor-draining lymph node and circulation. Also in breast cancer patients, T_reg levels were elevated upon ICB. Depletion of T_regs during neoadjuvant ICB in tumor-bearing mice not only reshaped the intratumoral immune landscape into a state favorable for ICB response but also induced profound and persistent alterations in systemic immunity, characterized by elevated CD8+ T cells and NK cells and durable T cell activation that was maintained after treatment cessation. While depletion of T_regs in combination with neoadjuvant ICB did not inhibit primary tumor growth, it prolonged metastasis-related survival driven predominantly by CD8+ T cells. This study demonstrates that neoadjuvant ICB therapy of breast cancer can be empowered by simultaneous targeting of T_regs, extending metastasis-related survival, independent of a primary tumor response.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2201147"},"PeriodicalIF":7.2,"publicationDate":"2023-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10114978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9391438","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":"Immunotherapy with IL12 and PD1/CTLA4 inhibition is effective in advanced ovarian cancer and associates with reversal of myeloid cell-induced immunosuppression.","authors":"Paul G Pavicic,&nbsp;Patricia A Rayman,&nbsp;Shadi Swaidani,&nbsp;Amit Rupani,&nbsp;Vladimir Makarov,&nbsp;Charles S Tannenbaum,&nbsp;Robert P Edwards,&nbsp;Anda M Vlad,&nbsp;C Marcela Diaz-Montero,&nbsp;Haider Mahdi","doi":"10.1080/2162402X.2023.2198185","DOIUrl":"10.1080/2162402X.2023.2198185","url":null,"abstract":"<p><p>The tumor microenvironment (TME) in ovarian cancer (OC) is characterized by immune suppression, due to an abundance of suppressive immune cells populations. To effectively enhance the activity of immune checkpoint inhibition (ICI), there is a need to identify agents that target these immunosuppressive networks while promoting the recruitment of effector T cells into the TME. To this end, we sought to investigate the effect of the immunomodulatory cytokine IL12 alone or in combination with dual-ICI (anti-PD1 + anti-CTLA4) on anti-tumor activity and survival, using the immunocompetent ID8-VEGF murine OC model. Detailed immunophenotyping of peripheral blood, ascites, and tumors revealed that durable treatment responses were associated with reversal of myeloid cell-induced immune suppression, which resulted in enhanced anti-tumor activity by T cells. Single cell transcriptomic analysis further demonstrated striking differences in the phenotype of myeloid cells from mice treated with IL12 in combination with dual-ICI. We also identified marked differences in treated mice that were in remission compared to those whose tumors progressed, further confirming a pivotal role for the modulation of myeloid cell function to allow for response to immunotherapy. These findings provide the scientific basis for the combination of IL12 and ICI to improve clinical response in OC.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2198185"},"PeriodicalIF":7.2,"publicationDate":"2023-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/7b/8c/KONI_12_2198185.PMC10101660.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9400742","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}