Oncoimmunology最新文献

{"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":"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}

{"title":"Rare immune-related adverse events in patients with melanoma: incidence, spectrum, and clinical presentations.","authors":"Benjamin C Park, Sathya Narayanan, Alexander Gavraldis, Fei Ye, Run Fan, Ryan J Sullivan, Genevieve Boland, Kerry L Reynolds, Justin M Balko, Matteo S Carlino, Georgina V Long, Leyre Zubiri, Alexander M Menzies, Douglas B Johnson","doi":"10.1080/2162402X.2023.2188719","DOIUrl":"10.1080/2162402X.2023.2188719","url":null,"abstract":"<p><p>Immune-related adverse events (irAEs) are side effects of immune checkpoint inhibitor therapy (ICI). While common irAEs have been well characterized, there are more limited data on rare immune related adverse events (RirAEs) due to low incidence. Lack of characterization of these entities has led to difficulties in accurate diagnosis and management. Here, we conducted a multi-institution analysis of all patients with stage III/IV melanoma who developed RirAEs after being treated with ICIs (anti-PD-1/L1, anti-CTLA-4, and combination PD-1/CTLA-4 blockade) at three institutions (Vanderbilt University Medical Center, Massachusetts General Hospital, and Melanoma Institute of Australia). RirAEs were defined as those occurring in approximately <1% of patients treated with anti-PD-1 or <2% with combination. Of 2834 patients who received ICIs, 82 developed RirAEs and were more common with combination PD-1/CTLA-4 blockade (4.6%) vs. anti-PD-1/L1 agents (2.8%). Overall median time from ICI start to RirAE was 86 days (interquartile range 42-235 days) with significantly earlier onset in combination therapy (<i>p</i> < 0.001). The spectrum of RirAEs spanned across several organ systems. Most RirAEs were grade 2 (57 [41.3%]) and grade 3 (40 [29.0%]) with relatively few grade 4 (11 [8.0%]) or 5 (5 [3.6%]) events. Steroid re-escalation (21.4%) or additional immunosuppression (13.8%) were commonly required. RirAE recurrence occurred in 22.6% with ICI rechallenge; 37.1% had new irAEs with rechallenge. In conclusion, RirAEs associated with ICIs in melanoma patients occurred, in aggregate, in 2-5% of patients treated with anti-PD-1-based therapy. Steroid re-escalation and alternative immunosuppression use were frequently required but fatal irAEs were fairly uncommon.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2188719"},"PeriodicalIF":7.2,"publicationDate":"2023-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/15/f7/KONI_12_2188719.PMC10012911.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9698172","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":"RBD- specific Th1 responses are associated with vaccine-induced protection against SARS-CoV-2 infection in patients with hematological malignancies.","authors":"Camille Bigenwald, Yacine Haddad, Cassandra Thelemaque, Agathe Carrier, Roxanne Birebent, Pierre Ly, Caroline Flament, Imran Lahmar, Eric de Sousa, Markus Maeurer, Makoto Miyara, Tarek Assi, Cristina Castilla-Llorente, Christophe Willekens, Céline Fayemi, Julien Lazarovici, Aurélien Marabelle, Lisa Derosa, Vincent Ribrag, Laurence Zitvogel","doi":"10.1080/2162402X.2022.2163785","DOIUrl":"10.1080/2162402X.2022.2163785","url":null,"abstract":"<p><p>The SARS-CoV-2 pandemic still represents a threat for immunosuppressed and hematological malignancy (HM) bearing patients, causing increased morbidity and mortality. Given the low anti-SARSCoV-2 IgG titers post-vaccination, the COVID-19 threat prompted the prophylactic use of engineered anti-SARS-CoV-2 monoclonal antibodies. In addition, potential clinical significance of T cell responses has been overlooked during the first waves of the pandemic, calling for additional in-depth studies. We reported that the polarity and the repertoire of T cell immune responses govern the susceptibility to SARS-CoV-2 infection in health care workers and solid cancer patients. Here, we longitudinally analyzed humoral and cellular immune responses at each BNT162b2 mRNA vaccine injection in 47 HM patients under therapy. Only one-third of HM, mostly multiple myeloma (MM) bearing patients, could mount S1-RBD-specific IgG responses following BNT162b2 mRNA vaccines. This vaccine elicited a S1-RBD-specific Th1 immune response in about 20% patients, mostly in MM and Hodgkin lymphoma, while exacerbating Th2 responses in the 10% cases that presented this recognition pattern at baseline (mostly rituximab-treated patients). Performing a third booster barely improved the percentage of patients developing an S1-RBD-specific Th1 immunity and failed to seroconvert additional HM patients. Finally, 16 patients were infected with SARS-CoV-2, of whom 6 developed a severe infection. Only S1-RBD-specific Th1 responses were associated with protection against SARS-CoV2 infection, while Th2 responses or anti-S1-RBD IgG titers failed to correlate with protection. These findings herald the paramount relevance of vaccine-induced Th1 immune responses in hematological malignancies.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2163785"},"PeriodicalIF":7.2,"publicationDate":"2023-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/39/cc/KONI_12_2163785.PMC9828759.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10753117","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":"CARD9 deficiency promotes pancreatic cancer growth by blocking dendritic cell maturation via SLC6A8-mediated creatine transport.","authors":"Cheng Tian,&nbsp;Huimin Yuan,&nbsp;Yi Lu,&nbsp;Henghui He,&nbsp;Qing Li,&nbsp;Senlin Li,&nbsp;Jian Yang,&nbsp;Mengheng Wang,&nbsp;Ruochen Xu,&nbsp;Qian Liu,&nbsp;Ming Xiang","doi":"10.1080/2162402X.2023.2204015","DOIUrl":"https://doi.org/10.1080/2162402X.2023.2204015","url":null,"abstract":"<p><p>Pancreatic cancer (PC) is featured with low survival rate and poor outcomes. Herein, we found that the expression of caspase-recruitment domain-containing protein 9 (CARD9), predominantly expressed in innate immune cells, was positively related to the prognosis of PC patients. CARD9-deficient PC mice exhibited rapider cancer progression and poorer survival rate. CARD9 knockout decreased dendritic cell (DC) maturation and impaired DC ability to activate T cells in vivo and in vitro. Adoptive DC transfer confirmed that the role of CARD9 deficiency in PC relied on DCs. Creatine was identified as the most significant differential metabolite between WT DCs and CARD9^-/- DCs wherein it played an essential role in maintaining DC maturation and function. CARD9 deficiency led to decreased creatine levels in DCs by inhibiting the transcription of the creatine-specific transporter, solute carrier family 6 member 8 (SLC6A8). Furtherly, CARD9 deletion blocked p65 activation by abolishing the formation of CARD9-BCL10-MALT1 complex, which prevented the binding between p65 and SLC6A8 promoter. These events decreased the creatine transport into DCs, and led to DC immaturity and impairment in antitumor immunity, consequently promoting PC progression.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2204015"},"PeriodicalIF":7.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/80/6c/KONI_12_2204015.PMC10120541.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9398018","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,&nbsp;Kevin Kos,&nbsp;Lorenzo Spagnuolo,&nbsp;Olga I Isaeva,&nbsp;Hannah Garner,&nbsp;Max D Wellenstein,&nbsp;Noor Bakker,&nbsp;Danique E M Duits,&nbsp;Kelly Kersten,&nbsp;Sjoerd Klarenbeek,&nbsp;Cheei-Sing Hau,&nbsp;Daphne Kaldenbach,&nbsp;Elisabeth A M Raeven,&nbsp;Kim Vrijland,&nbsp;Marleen Kok,&nbsp;Karin E de Visser","doi":"10.1080/2162402X.2023.2201147","DOIUrl":"https://doi.org/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":"2023-01-01","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}