Oncoimmunology最新文献

{"title":"HUNK as a key regulator of tumor-associated macrophages in triple negative breast cancer.","authors":"Nicole Ramos Solis, Anthony Cannon, Tinslee Dilday, Melissa Abt, Adrian L Oblak, Adam C Soloff, Mark H Kaplan, Elizabeth S Yeh","doi":"10.1080/2162402X.2024.2364382","DOIUrl":"10.1080/2162402X.2024.2364382","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC tumors are not sensitive to endocrine therapy, and standardized TNBC treatment regimens are lacking. TNBC is a more immunogenic subtype of breast cancer, making it more responsive to immunotherapy intervention. Tumor-associated macrophages (TAMs) constitute one of the most abundant immune cell populations in TNBC tumors and contribute to cancer metastasis. This study examines the role of the protein kinase HUNK in tumor immunity. Gene expression analysis using NanoString's nCounter PanCancer Immune Profiling panel identified that targeting HUNK is associated with changes in the IL-4/IL-4 R cytokine signaling pathway. Experimental analysis shows that HUNK kinase activity regulates IL-4 production in mammary tumor cells, and this regulation is dependent on STAT3. In addition, HUNK-dependent regulation of IL-4 secreted from tumor cells induces polarization of macrophages into an M2-like phenotype associated with TAMs. In return, IL-4 induces cancer metastasis and macrophages to produce epidermal growth factor. These findings delineate a paracrine signaling exchange between tumor cells and TAMs regulated by HUNK and dependent on IL-4/IL-4 R. This highlights the potential of HUNK as a target for reducing TNBC metastasis through modulation of the TAM population.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2364382"},"PeriodicalIF":6.5,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11155704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141285048","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":"β-Lapachone promotes the recruitment and polarization of tumor-associated neutrophils (TANs) toward an antitumor (N1) phenotype in NQO1-positive cancers.","authors":"Soumya Tumbath, Lingxiang Jiang, Xiaoguang Li, Taolan Zhang, Kashif Rafiq Zahid, Ye Zhao, Hao Zhou, Zhijun Yin, Tao Lu, Shu Jiang, Yaomin Chen, Xiang Chen, Yang-Xin Fu, Xiumei Huang","doi":"10.1080/2162402X.2024.2363000","DOIUrl":"10.1080/2162402X.2024.2363000","url":null,"abstract":"<p><p>NAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in most solid cancers, emerging as a promising target for tumor-selective killing. β-Lapachone (β-Lap), an NQO1 bioactivatable drug, exhibits significant antitumor effects on NQO1-positive cancer cells by inducing immunogenic cell death (ICD) and enhancing tumor immunogenicity. However, the interaction between β-Lap-mediated antitumor immune responses and neutrophils, novel antigen-presenting cells (APCs), remains unknown. This study demonstrates that β-Lap selectively kills NQO1-positive murine tumor cells by significantly increasing intracellular ROS formation and inducing DNA double strand breaks (DSBs), resulting in DNA damage. Treatment with β-Lap efficiently eradicates immunocompetent murine tumors and significantly increases the infiltration of tumor-associated neutrophils (TANs) into the tumor microenvironment (TME), which plays a crucial role in the drug's therapeutic efficacy. Further, the presence of β-Lap-induced antigen medium leads bone marrow-derived neutrophils (BMNs) to directly kill murine tumor cells, aiding in dendritic cells (DCs) recruitment and significantly enhancing CD8⁺ T cell proliferation. β-Lap treatment also drives the polarization of TANs toward an antitumor N1 phenotype, characterized by elevated IFN-β expression and reduced TGF-β cytokine expression, along with increased CD95 and CD54 surface markers. β-Lap treatment also induces N1 TAN-mediated T cell cross-priming. The HMGB1/TLR4/MyD88 signaling cascade influences neutrophil infiltration into β-Lap-treated tumors. Blocking this cascade or depleting neutrophil infiltration abolishes the antigen-specific T cell response induced by β-Lap treatment. Overall, this study provides comprehensive insights into the role of tumor-infiltrating neutrophils in the β-Lap-induced antitumor activity against NQO1-positive murine tumors.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2363000"},"PeriodicalIF":6.5,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11155710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141285049","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":"CD20 expression regulates CD37 levels in B-cell lymphoma - implications for immunotherapies.","authors":"Malgorzata Bobrowicz, Aleksandra Kusowska, Marta Krawczyk, Andriy Zhylko, Christopher Forcados, Aleksander Slusarczyk, Joanna Barankiewicz, Joanna Domagala, Matylda Kubacz, Michal Šmída, Lenka Dostalova, Katsiaryna Marhelava, Klaudyna Fidyt, Monika Pepek, Iwona Baranowska, Anna Szumera-Cieckiewicz, Else Marit Inderberg, Sébastien Wälchli, Monika Granica, Agnieszka Graczyk-Jarzynka, Martyna Majchrzak, Marcin Poreba, Carina Lynn Gehlert, Matthias Peipp, Malgorzata Firczuk, Monika Prochorec-Sobieszek, Magdalena Winiarska","doi":"10.1080/2162402X.2024.2362454","DOIUrl":"10.1080/2162402X.2024.2362454","url":null,"abstract":"<p><p>Rituximab (RTX) plus chemotherapy (R-CHOP) applied as a first-line therapy for lymphoma leads to a relapse in approximately 40% of the patients. Therefore, novel approaches to treat aggressive lymphomas are being intensively investigated. Several RTX-resistant (RR) cell lines have been established as surrogate models to study resistance to R-CHOP. Our study reveals that RR cells are characterized by a major downregulation of CD37, a molecule currently explored as a target for immunotherapy. Using CD20 knockout (KO) cell lines, we demonstrate that CD20 and CD37 form a complex, and hypothesize that the presence of CD20 stabilizes CD37 in the cell membrane. Consequently, we observe a diminished cytotoxicity of anti-CD37 monoclonal antibody (mAb) in complement-dependent cytotoxicity in both RR and CD20 KO cells that can be partially restored upon lysosome inhibition. On the other hand, the internalization rate of anti-CD37 mAb in CD20 KO cells is increased when compared to controls, suggesting unhampered efficacy of antibody drug conjugates (ADCs). Importantly, even a major downregulation in CD37 levels does not hamper the efficacy of CD37-directed chimeric antigen receptor (CAR) T cells. In summary, we present here a novel mechanism of CD37 regulation with further implications for the use of anti-CD37 immunotherapies.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2362454"},"PeriodicalIF":6.5,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11155707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141285047","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":"Clinically relevant GABARAP deficiency abrogates bortezomib-induced immunogenic cell death in multiple myeloma.","authors":"Liwei Zhao, Zhe Shen, Guido Kroemer, Oliver Kepp","doi":"10.1080/2162402X.2024.2360275","DOIUrl":"10.1080/2162402X.2024.2360275","url":null,"abstract":"<p><p>Recently, it was revealed that the high-risk, poor-prognosis downregulation of GABA type A receptor-associated protein (GABARAP) causes a defect in both autophagy and surface exposure of calreticulin (CALR) in multiple myeloma (MM) cells responding to bortezomib. Hence, GABARAP-defective MM cells fail to undergo immunogenic cell death.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2360275"},"PeriodicalIF":7.2,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11135808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175085","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":"Immunogenic oncolysis by tigilanol tiglate.","authors":"Jonathan G Pol, Manuela Lizarralde-Guerrero, Guido Kroemer","doi":"10.1080/2162402X.2024.2360230","DOIUrl":"10.1080/2162402X.2024.2360230","url":null,"abstract":"<p><p>Tigilanol tiglate is an oncolytic small molecule that is undergoing clinical trials. A recent study revealed the capacity of this pyroptosis inducer to elicit hallmarks of immunogenic cell death. In addition, intratumoral injection of tigilanol tiglate can sensitize subcutaneous cancers to subsequent immune checkpoint inhibitors targeting CTLA-4 alone or in combination with PD-1.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2360230"},"PeriodicalIF":7.2,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11135828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175660","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":"CXCL10 and IL15 co-expressing chimeric antigen receptor T cells enhance anti-tumor effects in gastric cancer by increasing cytotoxic effector cell accumulation and survival.","authors":"Siyue Nie, Yujie Song, Kun Hu, Wei Zu, Fengjiao Zhang, Lixia Chen, Qiang Ma, Zishan Zhou, Shunchang Jiao","doi":"10.1080/2162402X.2024.2358590","DOIUrl":"10.1080/2162402X.2024.2358590","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cells have demonstrated outstanding therapeutic success in hematological malignancies. Yet, their efficacy against solid tumors remains constrained due to inadequate infiltration of cytotoxic T and CAR-T cells in the tumor microenvironment (TME), a factor correlated with poor prognosis in patients with solid tumors. To overcome this limitation, we engineered CAR-T cells to secrete CXCL10 and IL15 (10 × 15 CAR-T), which sustain T cell viability and enhance their recruitment, thereby amplifying the long-term cytotoxic capacity of CAR-T cells in vitro. In a xenograft model employing NUGC4-T21 cells, mice receiving 10 × 15 CAR-T cells showed superior tumor reduction and extended survival rates compared to those treated with second-generation CAR-T cells. Histopathological evaluations indicated a pronounced increase in cytotoxic T cell accumulation in the TME post 10 × 15 CAR-T cell treatment. Therefore, the synergistic secretion of CXCL10 and IL15 in these CAR-T cells enhances T cell recruitment and adaptability within tumor tissues, improving tumor control. This approach may offer a promising strategy for advancing CAR-T therapies in the treatment of solid tumors.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2358590"},"PeriodicalIF":7.2,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11135867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175562","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":"HIF2A mediates lineage transition to aggressive phenotype of cancer-associated fibroblasts in lung cancer brain metastasis.","authors":"Muyuan You, Minjie Fu, Zhewei Shen, Yuan Feng, Licheng Zhang, Xianmin Zhu, Zhengping Zhuang, Ying Mao, Wei Hua","doi":"10.1080/2162402X.2024.2356942","DOIUrl":"10.1080/2162402X.2024.2356942","url":null,"abstract":"<p><p>Brain metastasis is the most devasting form of lung cancer. Recent studies highlight significant differences in the tumor microenvironment (TME) between lung cancer brain metastasis (LCBM) and primary lung cancer, which contribute significantly to tumor progression and drug resistance. Cancer-associated fibroblasts (CAFs) are the major component of pro-tumor TME with high plasticity. However, the lineage composition and function of CAFs in LCBM remain elusive. By reanalyzing single-cell RNA sequencing (scRNA-seq) data (GSE131907) from lung cancer patients with different stages of metastasis comprising primary lesions and brain metastasis, we found that CAFs undergo distinctive lineage transition during LCBM under a hypoxic situation, which is directly driven by hypoxia-induced HIF-2α activation. Transited CAFs enhance angiogenesis through VEGF pathways, trigger metabolic reprogramming, and promote the growth of tumor cells. Bulk RNA sequencing data was utilized as validation cohorts. Multiplex immunohistochemistry (mIHC) assay was performed on four paired samples of brain metastasis and their primary lung cancer counterparts to validate the findings. Our study revealed a novel mechanism of lung cancer brain metastasis featuring HIF-2α-induced lineage transition and functional alteration of CAFs, which offers potential therapeutic targets.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2356942"},"PeriodicalIF":6.5,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11110709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081863","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":"CPT1C-positive cancer-associated fibroblast facilitates immunosuppression through promoting IL-6-induced M2-like phenotype of macrophage.","authors":"Rongyuan Wei, Junquan Song, Hongda Pan, Xiaowen Liu, Jianpeng Gao","doi":"10.1080/2162402X.2024.2352179","DOIUrl":"10.1080/2162402X.2024.2352179","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) exhibit remarkable phenotypic heterogeneity, with specific subsets implicated in immunosuppression in various malignancies. However, whether and how they attenuate anti-tumor immunity in gastric cancer (GC) remains elusive. CPT1C, a unique isoform of carnitine palmitoyltransferase pivotal in regulating fatty acid oxidation, is briefly indicated as a protumoral metabolic mediator in the tumor microenvironment (TME) of GC. In the present study, we initially identified specific subsets of fibroblasts exclusively overexpressing CPT1C, hereby termed them as CPT1C⁺CAFs. Subsequent findings indicated that CPT1C⁺CAFs fostered a stroma-enriched and immunosuppressive TME as they correlated with extracellular matrix-related molecular features and enrichment of both immunosuppressive subsets, especially M2-like macrophages, and multiple immune-related pathways. Next, we identified that CPT1C⁺CAFs promoted the M2-like phenotype of macrophage <i>in vitro</i>. Bioinformatic analyses unveiled the robust IL-6 signaling between CPT1C⁺CAFs and M2-like phenotype of macrophage and identified CPT1C⁺CAFs as the primary source of IL-6. Meanwhile, suppressing CPT1C expression in CAFs significantly decreased IL-6 secretion <i>in vitro</i>. Lastly, we demonstrated the association of CPT1C⁺CAFs with therapeutic resistance. Notably, GC patients with high CPT1C⁺CAFs infiltration responded poorly to immunotherapy in clinical cohort. Collectively, our data not only present the novel identification of CPT1C⁺CAFs as immunosuppressive subsets in TME of GC, but also reveal the underlying mechanism that CPT1C⁺CAFs impair tumor immunity by secreting IL-6 to induce the immunosuppressive M2-like phenotype of macrophage in GC.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2352179"},"PeriodicalIF":7.2,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11093039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923656","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":"Characterization of innate lymphoid cell subsets infiltrating melanoma and epithelial ovarian tumors.","authors":"Douglas C Chung, Maryam Ghaedi, Kathrin Warner, Azin Sayad, Samuel D Saibil, Marcus Q Bernardini, Blaise A Clarke, Patricia A Shaw, Marcus O Butler, Alexandra Easson, Sorana Morrissy, Ben X Wang, Linh Nguyen, Pamela S Ohashi, Nicolas Jacquelot","doi":"10.1080/2162402X.2024.2349347","DOIUrl":"10.1080/2162402X.2024.2349347","url":null,"abstract":"<p><p>The innate lymphoid cell (ILC) family is composed of heterogeneous innate effector and helper immune cells that preferentially reside in tissues where they promote tissue homeostasis. In cancer, they have been implicated in driving both pro- and anti-tumor responses. This apparent dichotomy highlights the need to better understand differences in the ILC composition and phenotype within different tumor types that could drive seemingly opposite anti-tumor responses. Here, we characterized the frequency and phenotype of various ILC subsets in melanoma metastases and primary epithelial ovarian tumors. We observed high PD-1 expression on ILC subsets isolated from epithelial ovarian tumor samples, while ILC populations in melanoma samples express higher levels of LAG-3. In addition, we found that the frequency of cytotoxic ILCs and NKp46⁺ILC3 in tumors positively correlates with monocytic cells and conventional type 2 dendritic cells, revealing potentially new interconnected immune cell subsets in the tumor microenvironment. Consequently, these observations may have direct relevance to tumor microenvironment composition and how ILC subset may influence anti-tumor immunity.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2349347"},"PeriodicalIF":7.2,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11093043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923655","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":"Distinct autoantibody profiles across checkpoint inhibitor types and toxicities.","authors":"Hong Mu-Mosley, Mitchell S von Itzstein, Farjana Fattah, Jialiang Liu, Chengsong Zhu, Yang Xie, Edward K Wakeland, Jason Y Park, Brad S Kahl, Catherine S Diefenbach, David E Gerber","doi":"10.1080/2162402X.2024.2351255","DOIUrl":"10.1080/2162402X.2024.2351255","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI) are increasingly used in combination. To understand the effects of different ICI categories, we characterized changes in circulating autoantibodies in patients enrolled in the E4412 trial (NCT01896999) of brentuximab vedotin (BV) plus ipilimumab, BV plus nivolumab, or BV plus ipilimumab-nivolumab for Hodgkin Lymphoma. Cycle 2 Day 1 (C2D1) autoantibody levels were compared to pre-treatment baseline. Across 112 autoantibodies tested, we generally observed increases in ipilimumab-containing regimens, with decreases noted in the nivolumab arm. Among 15 autoantibodies with significant changes at C2D1, all nivolumab cases exhibited decreases, with more than 90% of ipilimumab-exposed cases showing increases. Autoantibody profiles also showed differences according to immune-related adverse event (irAE) type, with rash generally featuring increases and liver toxicity demonstrating decreases. We conclude that dynamic autoantibody profiles may differ according to ICI category and irAE type. These findings may have relevance to clinical monitoring and irAE treatment.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2351255"},"PeriodicalIF":7.2,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11085965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140913277","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}