Cancer-associated fibroblasts (CAFs) contribute to cancer initiation and progression and play a pivotal role in therapeutic response and patient prognosis. CAFs exhibit functional and phenotypic heterogeneity, highlighting the need to clarify the specific subtypes of CAFs to facilitate the development of targeted therapies against pro-tumorigenic CAFs. Here, using single-cell RNA sequencing on patient samples of esophageal squamous cell carcinoma (ESCC), we identified a CAF subcluster associated with tumor stemness that was enriched in genes associated with hypoxia and senescence. The CAF subpopulation, termed as hypoxia-induced senescent fibroblasts (hsCAFs), displayed high secretion of insulin-like growth factor 1 (IGF1). The hsCAFs inhibited AMP-activated protein kinase (AMPK) activity in cancer cells via IGF1 to promote tumor stemness. The formation of hsCAFs was induced by the synergetic effect of hypoxia and cancer cells. Activation of nuclear factor erythroid 2-related factor 2 (NRF2) in cancer cells under hypoxia drove interleukin-1 alpha (IL-1α) production to trigger CAF senescence and IGF1 secretion via nuclear factor I A (NFIA). Knockout of IGF1 in CAFs or NRF2 in ESCC cells suppressed the tumor growth and chemotherapy resistance induced by CAFs in vivo. Importantly, patients with high proportions of hsCAFs showed poor survival and a worse response to chemotherapy. In summary, these findings identify a hsCAF subpopulation generated by interplay between cancer cells and CAFs under hypoxic conditions that promotes ESCC stemness and reveal targeting hsCAFs as an effective therapeutic strategy against chemotherapy-resistant ESCC.
{"title":"Hypoxia-Induced Senescent Fibroblasts Secrete IGF1 to Promote Cancer Stemness in Esophageal Squamous Cell Carcinoma","authors":"Zhengjie Ou, Liang Zhu, Xinjie Chen, Tianyuan Liu, Guoyu Cheng, Rucheng Liu, Shaosen Zhang, Wen Tan, Dongxin Lin, Chen Wu","doi":"10.1158/0008-5472.can-24-1185","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1185","url":null,"abstract":"Cancer-associated fibroblasts (CAFs) contribute to cancer initiation and progression and play a pivotal role in therapeutic response and patient prognosis. CAFs exhibit functional and phenotypic heterogeneity, highlighting the need to clarify the specific subtypes of CAFs to facilitate the development of targeted therapies against pro-tumorigenic CAFs. Here, using single-cell RNA sequencing on patient samples of esophageal squamous cell carcinoma (ESCC), we identified a CAF subcluster associated with tumor stemness that was enriched in genes associated with hypoxia and senescence. The CAF subpopulation, termed as hypoxia-induced senescent fibroblasts (hsCAFs), displayed high secretion of insulin-like growth factor 1 (IGF1). The hsCAFs inhibited AMP-activated protein kinase (AMPK) activity in cancer cells via IGF1 to promote tumor stemness. The formation of hsCAFs was induced by the synergetic effect of hypoxia and cancer cells. Activation of nuclear factor erythroid 2-related factor 2 (NRF2) in cancer cells under hypoxia drove interleukin-1 alpha (IL-1α) production to trigger CAF senescence and IGF1 secretion via nuclear factor I A (NFIA). Knockout of IGF1 in CAFs or NRF2 in ESCC cells suppressed the tumor growth and chemotherapy resistance induced by CAFs in vivo. Importantly, patients with high proportions of hsCAFs showed poor survival and a worse response to chemotherapy. In summary, these findings identify a hsCAF subpopulation generated by interplay between cancer cells and CAFs under hypoxic conditions that promotes ESCC stemness and reveal targeting hsCAFs as an effective therapeutic strategy against chemotherapy-resistant ESCC.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"14 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-10DOI: 10.1158/0008-5472.CAN-24-2450
Apurva Pandey, Peter J Rohweder, Lieza M Chan, Chayanid Ongpipattanakul, Dong Hee Chung, Bryce Paolella, Fiona M Quimby, Ngoc Nguyen, Kliment A Verba, Michael J Evans, Charles S Craik
Antibody-based therapies have emerged as a powerful strategy for the management of diverse cancers. Unfortunately, tumor-specific antigens remain challenging to identify and target. Recent work established that inhibitor-modified peptide adducts derived from KRAS G12C are competent for antigen presentation via MHC I and can be targeted by antibody-based therapeutics, offering a means to directly target an intracellular oncoprotein at the cell surface with combination therapies. Here, we validated antigen display of "haptenated" KRAS G12C peptide fragments on tumors in mouse models treated with the FDA-approved KRAS G12C covalent inhibitor Sotorasib using PET/CT imaging of an 89Zr-labeled P1B7 IgG antibody, which selectively binds Sotorasib-modified KRAS G12C MHC I complexes. Targeting this peptide-MHC I complex with radioligand therapy using 225Ac- or 177Lu-P1B7 IgG effectively inhibited tumor growth in combination with Sotorasib. Elucidation of the 3.1 Å cryo-EM structure of P1B7 bound to a haptenated KRAS G12C peptide-MHC I complex confirmed that the Sotorasib-modified KRAS G12C peptide is presented via a canonical binding pose and showed that P1B7 binds the complex in a T-cell receptor-like manner. Together, these findings demonstrate the potential value of targeting unique oncoprotein-derived, haptenated MHC I complexes with radioligand therapeutics and provide a structural framework for developing next generation antibodies.
{"title":"Therapeutic Targeting and Structural Characterization of a Sotorasib-Modified KRAS G12C-MHC I complex Demonstrates the Antitumor Efficacy of Hapten-Based Strategies.","authors":"Apurva Pandey, Peter J Rohweder, Lieza M Chan, Chayanid Ongpipattanakul, Dong Hee Chung, Bryce Paolella, Fiona M Quimby, Ngoc Nguyen, Kliment A Verba, Michael J Evans, Charles S Craik","doi":"10.1158/0008-5472.CAN-24-2450","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-2450","url":null,"abstract":"<p><p>Antibody-based therapies have emerged as a powerful strategy for the management of diverse cancers. Unfortunately, tumor-specific antigens remain challenging to identify and target. Recent work established that inhibitor-modified peptide adducts derived from KRAS G12C are competent for antigen presentation via MHC I and can be targeted by antibody-based therapeutics, offering a means to directly target an intracellular oncoprotein at the cell surface with combination therapies. Here, we validated antigen display of \"haptenated\" KRAS G12C peptide fragments on tumors in mouse models treated with the FDA-approved KRAS G12C covalent inhibitor Sotorasib using PET/CT imaging of an 89Zr-labeled P1B7 IgG antibody, which selectively binds Sotorasib-modified KRAS G12C MHC I complexes. Targeting this peptide-MHC I complex with radioligand therapy using 225Ac- or 177Lu-P1B7 IgG effectively inhibited tumor growth in combination with Sotorasib. Elucidation of the 3.1 Å cryo-EM structure of P1B7 bound to a haptenated KRAS G12C peptide-MHC I complex confirmed that the Sotorasib-modified KRAS G12C peptide is presented via a canonical binding pose and showed that P1B7 binds the complex in a T-cell receptor-like manner. Together, these findings demonstrate the potential value of targeting unique oncoprotein-derived, haptenated MHC I complexes with radioligand therapeutics and provide a structural framework for developing next generation antibodies.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09DOI: 10.1158/0008-5472.can-24-2608
Shripad V. Bhagwat, Cecilia Mur, Matthew Vandekopple, Baohui Zhao, Weihua Shen, Carlos Marugán, Andrew Capen, Lisa Kindler, Jennifer R. Stephens, Lysiane Huber, Mark A. Castanares, David Garcia-Tapia, Jeff D. Cohen, Jolie Bastian, Brian Mattioni, Eunice Yuen, Thomas K. Baker, Vivian Rodriguez Cruz, Dongling Fei, Jason R. Manro, Nicholas Pulliam, Michele S. Dowless, Maria Jesus. Ortiz Ruiz, Chunping Yu, Loredana Puca, Anke Klippel, Francesca Bacchion, Roohi Ismail-Khan, Vanessa Rodrik-Outmezguine, Sheng-Bin Peng, María Jose Lallena, Xueqian Gong, Alfonso de Dios
Targeting of the estrogen receptor (ER) by anti-estrogens is the standard-of-care for patients with ER+ HER2- advanced/metastatic breast cancer. While anti-estrogens that degrade ERα (fulvestrant) or block estrogen production (aromatase inhibitors) have improved patient outcomes, clinically important challenges remain related to drug administration, limited bioavailability, lack of brain exposure, and acquired resistance due to ESR1 mutations. These limitations indicate a need for more robust ER-targeted therapies. Here, we discovered and characterized imlunestrant, a next-generation potent, brain-penetrant oral selective estrogen receptor degrader (SERD). Imlunestrant degraded ERα and decreased ERα-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wildtype and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status. In an ER+ breast cancer intracranial tumor model, imlunestrant prolonged survival compared to vehicle or alternative SERD therapies. Together, these finding support the potential of imlunestrant to degrade ERα and suppress the growth of ESR1 wildtype and mutant breast cancer, including brain metastatic tumors.
{"title":"Imlunestrant is an Oral, Brain-Penetrant Selective Estrogen Receptor Degrader with Potent Antitumor Activity in ESR1 Wildtype and Mutant Breast Cancer","authors":"Shripad V. Bhagwat, Cecilia Mur, Matthew Vandekopple, Baohui Zhao, Weihua Shen, Carlos Marugán, Andrew Capen, Lisa Kindler, Jennifer R. Stephens, Lysiane Huber, Mark A. Castanares, David Garcia-Tapia, Jeff D. Cohen, Jolie Bastian, Brian Mattioni, Eunice Yuen, Thomas K. Baker, Vivian Rodriguez Cruz, Dongling Fei, Jason R. Manro, Nicholas Pulliam, Michele S. Dowless, Maria Jesus. Ortiz Ruiz, Chunping Yu, Loredana Puca, Anke Klippel, Francesca Bacchion, Roohi Ismail-Khan, Vanessa Rodrik-Outmezguine, Sheng-Bin Peng, María Jose Lallena, Xueqian Gong, Alfonso de Dios","doi":"10.1158/0008-5472.can-24-2608","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2608","url":null,"abstract":"Targeting of the estrogen receptor (ER) by anti-estrogens is the standard-of-care for patients with ER+ HER2- advanced/metastatic breast cancer. While anti-estrogens that degrade ERα (fulvestrant) or block estrogen production (aromatase inhibitors) have improved patient outcomes, clinically important challenges remain related to drug administration, limited bioavailability, lack of brain exposure, and acquired resistance due to ESR1 mutations. These limitations indicate a need for more robust ER-targeted therapies. Here, we discovered and characterized imlunestrant, a next-generation potent, brain-penetrant oral selective estrogen receptor degrader (SERD). Imlunestrant degraded ERα and decreased ERα-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wildtype and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status. In an ER+ breast cancer intracranial tumor model, imlunestrant prolonged survival compared to vehicle or alternative SERD therapies. Together, these finding support the potential of imlunestrant to degrade ERα and suppress the growth of ESR1 wildtype and mutant breast cancer, including brain metastatic tumors.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"5 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09DOI: 10.1158/0008-5472.can-24-2052
Joonatan Sipola, Aslı D. Munzur, Edmond M. Kwan, Clara C. Y. Seo, Benjamin J. Hauk, Karan Parekh, Yi Jou (Ruby) Liao, Cecily Q. Bernales, Gráinne Donnellan, Ingrid Bloise, Emily Fung, Sarah W.S. Ng, Gang Wang, Gillian Vandekerkhove, Matti Nykter, Matti Annala, Corinne Maurice-Dror, Kim N. Chi, Cameron Herberts, Alexander W. Wyatt, David Y. Takeda
Cell phenotype underlies prostate cancer presentation and treatment resistance and can be regulated by epigenomic features. However, the osteotropic tendency of prostate cancer limits access to metastatic tissue, meaning most prior insights into prostate cancer chromatin biology are from preclinical models that do not fully represent disease complexity. Noninvasive chromatin immunoprecipitation of histones in plasma cell-free in humans may enable capture of disparate prostate cancer phenotypes. Here, we analyzed activating promoter- and enhancer-associated H3K4me2 from cfDNA in metastatic prostate cancer enriched for divergent patterns of metastasis and diverse clinical presentation. H3K4me2 density across prostate cancer genes, accessible chromatin, and lineage-defining transcription factor binding sites correlated strongly with circulating tumor DNA (ctDNA) fraction—demonstrating capture of prostate cancer-specific biology and informing the development of a statistical framework to adjust for ctDNA fraction. Chromatin hallmarks mirrored synchronously measured clinico-genomic features: bone versus liver-predominant disease, serum PSA, biopsy-confirmed histopathological subtype, and RB1 deletions convergently indicated phenotype segregation along an axis of differential androgen receptor activity and neuroendocrine identity. Detection of lineage switching after sequential progression on systemic therapy in select patients indicates potential utility for individualized resistance monitoring. Epigenomic footprints of metastasis-induced normal tissue destruction were evident in bulk cfDNA from two patients. Finally, a public epigenomic resource was generated using a distinct chromatin marker that has not been widely investigated in prostate cancer. These results provide insight into the adaptive molecular landscape of aggressive prostate cancer and endorse plasma cfDNA chromatin profiling as a biomarker source and biological discovery tool.
{"title":"Plasma cell-free DNA chromatin immunoprecipitation profiling depicts phenotypic and clinical heterogeneity in advanced prostate cancer","authors":"Joonatan Sipola, Aslı D. Munzur, Edmond M. Kwan, Clara C. Y. Seo, Benjamin J. Hauk, Karan Parekh, Yi Jou (Ruby) Liao, Cecily Q. Bernales, Gráinne Donnellan, Ingrid Bloise, Emily Fung, Sarah W.S. Ng, Gang Wang, Gillian Vandekerkhove, Matti Nykter, Matti Annala, Corinne Maurice-Dror, Kim N. Chi, Cameron Herberts, Alexander W. Wyatt, David Y. Takeda","doi":"10.1158/0008-5472.can-24-2052","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2052","url":null,"abstract":"Cell phenotype underlies prostate cancer presentation and treatment resistance and can be regulated by epigenomic features. However, the osteotropic tendency of prostate cancer limits access to metastatic tissue, meaning most prior insights into prostate cancer chromatin biology are from preclinical models that do not fully represent disease complexity. Noninvasive chromatin immunoprecipitation of histones in plasma cell-free in humans may enable capture of disparate prostate cancer phenotypes. Here, we analyzed activating promoter- and enhancer-associated H3K4me2 from cfDNA in metastatic prostate cancer enriched for divergent patterns of metastasis and diverse clinical presentation. H3K4me2 density across prostate cancer genes, accessible chromatin, and lineage-defining transcription factor binding sites correlated strongly with circulating tumor DNA (ctDNA) fraction—demonstrating capture of prostate cancer-specific biology and informing the development of a statistical framework to adjust for ctDNA fraction. Chromatin hallmarks mirrored synchronously measured clinico-genomic features: bone versus liver-predominant disease, serum PSA, biopsy-confirmed histopathological subtype, and RB1 deletions convergently indicated phenotype segregation along an axis of differential androgen receptor activity and neuroendocrine identity. Detection of lineage switching after sequential progression on systemic therapy in select patients indicates potential utility for individualized resistance monitoring. Epigenomic footprints of metastasis-induced normal tissue destruction were evident in bulk cfDNA from two patients. Finally, a public epigenomic resource was generated using a distinct chromatin marker that has not been widely investigated in prostate cancer. These results provide insight into the adaptive molecular landscape of aggressive prostate cancer and endorse plasma cfDNA chromatin profiling as a biomarker source and biological discovery tool.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"140 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09DOI: 10.1158/0008-5472.can-24-1875
David Allard, Jeanne Cormery, Salma Bricha, Camille Fuselier, Farnoosh Abbas Aghababazadeh, Lucie Giraud, Emma Skora, Benjamin Haibe-Kains, John Stagg
Immunosuppression by adenosine is an important cancer immune checkpoint. Extracellular adenosine signals through specific receptors and can be transported across the cell membrane through nucleoside transporters. While adenosine receptors are well-known to regulate tumor immunity, the impact of adenosine transporters remains unexplored. In this study, we investigated the effect on tumor immunity of equilibrative nucleoside transporter-1 (ENT1), the major regulator of extracellular adenosine concentrations. Blocking or deleting host ENT1 significantly enhanced CD8+ T cell-dependent antitumor responses. Tumors inoculated into ENT1-deficient mice showed increased infiltration of effector CD8+ T cells with an enhanced cytotoxic transcriptomic profile and significant upregulation of granzyme B, IFN-γ, IL-2, TNF-α, and CXCL10. ENT1-deficiency was further associated with decreased tumor-infiltrating T regulatory cells and CD206high macrophages and suppressed CCL17 production. ENT1-deficiency notably potentiated the therapeutic activity of PD-1 blockade. T cells upregulated ENT1 upon activation, and blocking ENT1 enhanced their function when co-cultured with cognate antigen/HLA-matched melanoma cells. Mechanistically, ENT1-mediated adenosine uptake inhibited the activity of phosphoribosyl pyrophosphate synthetase (PRPS) in activated T cells, thereby suppressing production of uridine 5′-monophosphate (UMP) and its derivatives required for DNA and RNA synthesis. In summary, this study identified ENT1-mediated adenosine uptake as an important mechanism of adenosine-mediated immunosuppression and pyrimidine starvation that can be targeted to enhance antitumor T cell responses.
{"title":"Adenosine Uptake through the Nucleoside Transporter ENT1 Suppresses Antitumor Immunity and T Cell Pyrimidine Synthesis","authors":"David Allard, Jeanne Cormery, Salma Bricha, Camille Fuselier, Farnoosh Abbas Aghababazadeh, Lucie Giraud, Emma Skora, Benjamin Haibe-Kains, John Stagg","doi":"10.1158/0008-5472.can-24-1875","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1875","url":null,"abstract":"Immunosuppression by adenosine is an important cancer immune checkpoint. Extracellular adenosine signals through specific receptors and can be transported across the cell membrane through nucleoside transporters. While adenosine receptors are well-known to regulate tumor immunity, the impact of adenosine transporters remains unexplored. In this study, we investigated the effect on tumor immunity of equilibrative nucleoside transporter-1 (ENT1), the major regulator of extracellular adenosine concentrations. Blocking or deleting host ENT1 significantly enhanced CD8+ T cell-dependent antitumor responses. Tumors inoculated into ENT1-deficient mice showed increased infiltration of effector CD8+ T cells with an enhanced cytotoxic transcriptomic profile and significant upregulation of granzyme B, IFN-γ, IL-2, TNF-α, and CXCL10. ENT1-deficiency was further associated with decreased tumor-infiltrating T regulatory cells and CD206high macrophages and suppressed CCL17 production. ENT1-deficiency notably potentiated the therapeutic activity of PD-1 blockade. T cells upregulated ENT1 upon activation, and blocking ENT1 enhanced their function when co-cultured with cognate antigen/HLA-matched melanoma cells. Mechanistically, ENT1-mediated adenosine uptake inhibited the activity of phosphoribosyl pyrophosphate synthetase (PRPS) in activated T cells, thereby suppressing production of uridine 5′-monophosphate (UMP) and its derivatives required for DNA and RNA synthesis. In summary, this study identified ENT1-mediated adenosine uptake as an important mechanism of adenosine-mediated immunosuppression and pyrimidine starvation that can be targeted to enhance antitumor T cell responses.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"9 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09DOI: 10.1158/0008-5472.can-24-2223
Hao Chi, Shouyan Deng, Ke Xu, Yibo Zhang, Teng Song, Jianghong Yu, Yiting Wang, Jiayang Liu, Yuan Zhang, Jiawei Shi, Yungang Wang, Jie Xu
T cells within the tumor microenvironment frequently exhibit dysfunctional characteristics that compromise their ability to elicit both innate and therapeutic-induced immune responses. Regulators of immune dysfunction represent therapeutic targets to activate anti-tumor immunity. In this study, we identified semaphorin 3G (SEMA3G) as a key regulator of immune responses in cancer. SEMA3G was widely upregulated in diverse human cancers, and its expression was positively correlated with tumor progression. SEMA3G acted as a ligand that inhibited the activation and functionality of T cells. A comprehensive receptor screening approach demonstrated that SEMA3G exhibited a significantly stronger affinity for neuropilin NRP1 compared to NRP2. Furthermore, SEMA3G primarily impeded T-cell functions via NRP1. Disruption of SEMA3G using CRISPR/Cas9 technology or blockade with a neutralizing antibody effectively restored the cytotoxicity of CD8+ T cells and inhibited the growth of tumors in vivo. This research underscores the role of SEMA3G in T-cell dysfunction within tumors and proposes a targeting SEMA3G as a cancer immunotherapeutic strategy.
肿瘤微环境中的 T 细胞经常表现出功能失调的特征，从而影响其激发先天性免疫反应和治疗诱导性免疫反应的能力。免疫功能失调的调节因子是激活抗肿瘤免疫的治疗靶点。在这项研究中，我们发现半隐形蛋白3G（SEMA3G）是癌症免疫反应的关键调节因子。SEMA3G在多种人类癌症中广泛上调，其表达与肿瘤进展呈正相关。SEMA3G是一种配体，可抑制T细胞的活化和功能。一种全面的受体筛选方法表明，与 NRP2 相比，SEMA3G 对神经蛋白 NRP1 的亲和力明显更强。此外，SEMA3G 主要通过 NRP1 阻碍 T 细胞的功能。利用CRISPR/Cas9技术破坏SEMA3G或用中和抗体阻断SEMA3G，可有效恢复CD8+ T细胞的细胞毒性并抑制体内肿瘤的生长。这项研究强调了SEMA3G在肿瘤内T细胞功能障碍中的作用，并提出了以SEMA3G为靶点的癌症免疫治疗策略。
{"title":"SEMA3G-NRP1 Signaling Functions as an Immune Checkpoint that Enables Tumor Immune Evasion by Impairing T Cell Cytotoxicity","authors":"Hao Chi, Shouyan Deng, Ke Xu, Yibo Zhang, Teng Song, Jianghong Yu, Yiting Wang, Jiayang Liu, Yuan Zhang, Jiawei Shi, Yungang Wang, Jie Xu","doi":"10.1158/0008-5472.can-24-2223","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2223","url":null,"abstract":"T cells within the tumor microenvironment frequently exhibit dysfunctional characteristics that compromise their ability to elicit both innate and therapeutic-induced immune responses. Regulators of immune dysfunction represent therapeutic targets to activate anti-tumor immunity. In this study, we identified semaphorin 3G (SEMA3G) as a key regulator of immune responses in cancer. SEMA3G was widely upregulated in diverse human cancers, and its expression was positively correlated with tumor progression. SEMA3G acted as a ligand that inhibited the activation and functionality of T cells. A comprehensive receptor screening approach demonstrated that SEMA3G exhibited a significantly stronger affinity for neuropilin NRP1 compared to NRP2. Furthermore, SEMA3G primarily impeded T-cell functions via NRP1. Disruption of SEMA3G using CRISPR/Cas9 technology or blockade with a neutralizing antibody effectively restored the cytotoxicity of CD8+ T cells and inhibited the growth of tumors in vivo. This research underscores the role of SEMA3G in T-cell dysfunction within tumors and proposes a targeting SEMA3G as a cancer immunotherapeutic strategy.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"37 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09DOI: 10.1158/0008-5472.can-24-0456
Rigney E. Turnham, Adriana Pitea, Gwendolyn M. Jang, Zhong Xu, Huat Chye Lim, Alex L. Choi, John Von Dollen, Rebecca S. Levin, James T. Webber, Elizabeth McCarthy, Junjie Hu, Xiaolei Li, Li Che, Ananya Singh, Alex Yoon, Gary Chan, Robin K. Kelley, Danielle L. Swaney, Wei Zhang, Sourav Bandyopadhyay, Fabian J. Theis, Manon Eckhardt, Xin Chen, Kevan M. Shokat, Trey Ideker, Nevan J. Krogan, John D. Gordan
Hepatitis B virus (HBV) infections promote liver cancer initiation by inducing inflammation and cellular stress. Despite the primarily indirect effect on oncogenesis, HBV is associated with a recurrent genomic phenotype in HCC, suggesting that it impacts the biology of established HCC. Characterization of the interaction of HBV with host proteins and the mechanistic contributions of HBV to HCC initiation and maintenance could provide insights into HCC biology and uncover therapeutic vulnerabilities. Here, we used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human proteins in hepatocellular carcinoma (HCC). A subset of the host factors targeted by HBV proteins were preferentially mutated in non-HBV-associated HCC, suggesting that their interaction with HBV influences HCC biology. HBV interacted with proteins involved in mRNA splicing, mitogenic signaling, and DNA repair, with the latter set interacting with the HBV oncoprotein X (HBx). HBx remodeled the PP2A phosphatase complex by excluding striatin regulatory subunits from the PP2A holoenzyme, and the HBx effects on PP2A caused Hippo kinase activation. In parallel, HBx activated mTOR complex 2 (mTORC2), which can prevent YAP degradation. mTORC2-mediated upregulation of YAP was observed in human HCC specimens and mouse HCC models and could be targeted with mTOR kinase inhibitors. Thus, HBV interaction with host proteins rewires HCC signaling rather than directly activating mitogenic pathways, provide an alternative paradigm for the cellular effects of a tumor promoting virus.
{"title":"HBV Remodels PP2A Complexes to Rewire Kinase Signaling in Hepatocellular Carcinoma","authors":"Rigney E. Turnham, Adriana Pitea, Gwendolyn M. Jang, Zhong Xu, Huat Chye Lim, Alex L. Choi, John Von Dollen, Rebecca S. Levin, James T. Webber, Elizabeth McCarthy, Junjie Hu, Xiaolei Li, Li Che, Ananya Singh, Alex Yoon, Gary Chan, Robin K. Kelley, Danielle L. Swaney, Wei Zhang, Sourav Bandyopadhyay, Fabian J. Theis, Manon Eckhardt, Xin Chen, Kevan M. Shokat, Trey Ideker, Nevan J. Krogan, John D. Gordan","doi":"10.1158/0008-5472.can-24-0456","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0456","url":null,"abstract":"Hepatitis B virus (HBV) infections promote liver cancer initiation by inducing inflammation and cellular stress. Despite the primarily indirect effect on oncogenesis, HBV is associated with a recurrent genomic phenotype in HCC, suggesting that it impacts the biology of established HCC. Characterization of the interaction of HBV with host proteins and the mechanistic contributions of HBV to HCC initiation and maintenance could provide insights into HCC biology and uncover therapeutic vulnerabilities. Here, we used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human proteins in hepatocellular carcinoma (HCC). A subset of the host factors targeted by HBV proteins were preferentially mutated in non-HBV-associated HCC, suggesting that their interaction with HBV influences HCC biology. HBV interacted with proteins involved in mRNA splicing, mitogenic signaling, and DNA repair, with the latter set interacting with the HBV oncoprotein X (HBx). HBx remodeled the PP2A phosphatase complex by excluding striatin regulatory subunits from the PP2A holoenzyme, and the HBx effects on PP2A caused Hippo kinase activation. In parallel, HBx activated mTOR complex 2 (mTORC2), which can prevent YAP degradation. mTORC2-mediated upregulation of YAP was observed in human HCC specimens and mouse HCC models and could be targeted with mTOR kinase inhibitors. Thus, HBV interaction with host proteins rewires HCC signaling rather than directly activating mitogenic pathways, provide an alternative paradigm for the cellular effects of a tumor promoting virus.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"9 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09DOI: 10.1158/0008-5472.can-24-2341
Thomas Welte, Veena K. Vuttaradhi, Eleonora Y. Khlebus, Allison Brodsky, Alejandra Flores Legarreta, Joseph Celestino, Reid T. Powell, Clifford C. Stephan, Nghi Nguyen, Jian Li, Shiro Takamatsu, Katherine Calzoncinth, Anil K. Sood, David M. Gershenson, P. Andrew Futreal, Barrett Lawson, Robert Tyler. Hillman
Adult type ovarian granulosa cell tumors (AGCTs) are rare malignancies with the near universal c.C402G (p.Cys134Trp) somatic mutation in FOXL2, a Forkhead box-family transcription factor important for ovarian function. Relapsed AGCT is incurable, but the mechanism of the unique FOXL2 mutation could confer therapeutic vulnerabilities. To identify FOXL2-C134W-dependent pharmacologic synergies, we created and characterized endogenous FOXL2 isogenic AGCT cells and an AGCT tumoroid biobank. A drug screen identified that glucocorticoids promote FOXL2-C134W-dependent AGCT growth. Epigenetic investigation revealed that the Cys134Trp mutation exposes latent DNA sequence-specific chromatin remodeling activity in FOXL2. FOXL2-C134W-dependent chromatin remodeling activity redirected glucocorticoid receptor chromatin occupancy to drive hyaluronan synthase 2 gene expression and increase extracellular hyaluronan secretion. Treatment of AGCT models with hyaluronidase reduced viability, and dexamethasone rescued this effect. Combinatorial drug-drug interaction experiments demonstrated that dexamethasone antagonizes the potency of paclitaxel, a chemotherapy agent frequently used in the treatment of AGCT. Thus, gain-of-function pioneering activity contributes to the oncogenic mechanism of FOXL2-C134W and creates a potentially targetable synergy with glucocorticoid signaling.
{"title":"Gain-of-Function Chromatin Remodeling Activity of Oncogenic FOXL2-C134W Reprograms Glucocorticoid Receptor Occupancy to Drive Granulosa Cell Tumors","authors":"Thomas Welte, Veena K. Vuttaradhi, Eleonora Y. Khlebus, Allison Brodsky, Alejandra Flores Legarreta, Joseph Celestino, Reid T. Powell, Clifford C. Stephan, Nghi Nguyen, Jian Li, Shiro Takamatsu, Katherine Calzoncinth, Anil K. Sood, David M. Gershenson, P. Andrew Futreal, Barrett Lawson, Robert Tyler. Hillman","doi":"10.1158/0008-5472.can-24-2341","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2341","url":null,"abstract":"Adult type ovarian granulosa cell tumors (AGCTs) are rare malignancies with the near universal c.C402G (p.Cys134Trp) somatic mutation in FOXL2, a Forkhead box-family transcription factor important for ovarian function. Relapsed AGCT is incurable, but the mechanism of the unique FOXL2 mutation could confer therapeutic vulnerabilities. To identify FOXL2-C134W-dependent pharmacologic synergies, we created and characterized endogenous FOXL2 isogenic AGCT cells and an AGCT tumoroid biobank. A drug screen identified that glucocorticoids promote FOXL2-C134W-dependent AGCT growth. Epigenetic investigation revealed that the Cys134Trp mutation exposes latent DNA sequence-specific chromatin remodeling activity in FOXL2. FOXL2-C134W-dependent chromatin remodeling activity redirected glucocorticoid receptor chromatin occupancy to drive hyaluronan synthase 2 gene expression and increase extracellular hyaluronan secretion. Treatment of AGCT models with hyaluronidase reduced viability, and dexamethasone rescued this effect. Combinatorial drug-drug interaction experiments demonstrated that dexamethasone antagonizes the potency of paclitaxel, a chemotherapy agent frequently used in the treatment of AGCT. Thus, gain-of-function pioneering activity contributes to the oncogenic mechanism of FOXL2-C134W and creates a potentially targetable synergy with glucocorticoid signaling.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"20 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ARID1A, a core constituent of SWI/SNF complex, is mutated in approximately 10% of colorectal cancers (CRC). While ARID1A deficiency corresponds to heightened immune activity in CRC, immune checkpoint inhibitors (ICIs) have shown limited efficacy in these tumors. The discovery of targetable vulnerabilities associated with ARID1A deficiency in CRC could expand treatment options for patients. In this study, we demonstrated that arachidonic acid metabolism inhibitors synergize with ICIs in ARID1A-deficient CRC by enhancing the activity of CD8+ T cells and inhibiting vasculogenic mimicry (VM). Epigenetic analysis using ATAC-seq and ChIP-qPCR revealed that the lack of ARID1A results in reduced levels of PTGS1 and PTGS2, the key enzymes that control the arachidonic acid pathway. Low PTGS1 and PTGS2 expression generated a reliance on the remaining functionality of the arachidonic acid pathway in ARID1A-deficient cells. The arachidonic acid pathway inhibitor aspirin selectively inhibited the growth of ARID1A-deficient CRC, and aspirin sensitized tumors lacking ARID1A to immunotherapy. Together, these findings suggest that blocking arachidonic acid metabolism can enhance immune responses against tumors by activating CD8+ T cells and inhibiting VM, which synergizes with ICIs to improve treatment of ARID1A-deficient CRC.
{"title":"Targeting Arachidonic Acid Metabolism Enhances Immunotherapy Efficacy in ARID1A-Deficient Colorectal Cancer","authors":"Luying Cui, Ruiqi Liu, Shuling Han, Chunhui Zhang, Bojun Wang, Yuli Ruan, Xuefan Yu, Yien Li, Yuanfei Yao, Xin Guan, Yuanyu Liao, Dan Su, Yue Ma, Shuijie Li, Chao Liu, Yanqiao Zhang","doi":"10.1158/0008-5472.can-24-1611","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1611","url":null,"abstract":"ARID1A, a core constituent of SWI/SNF complex, is mutated in approximately 10% of colorectal cancers (CRC). While ARID1A deficiency corresponds to heightened immune activity in CRC, immune checkpoint inhibitors (ICIs) have shown limited efficacy in these tumors. The discovery of targetable vulnerabilities associated with ARID1A deficiency in CRC could expand treatment options for patients. In this study, we demonstrated that arachidonic acid metabolism inhibitors synergize with ICIs in ARID1A-deficient CRC by enhancing the activity of CD8+ T cells and inhibiting vasculogenic mimicry (VM). Epigenetic analysis using ATAC-seq and ChIP-qPCR revealed that the lack of ARID1A results in reduced levels of PTGS1 and PTGS2, the key enzymes that control the arachidonic acid pathway. Low PTGS1 and PTGS2 expression generated a reliance on the remaining functionality of the arachidonic acid pathway in ARID1A-deficient cells. The arachidonic acid pathway inhibitor aspirin selectively inhibited the growth of ARID1A-deficient CRC, and aspirin sensitized tumors lacking ARID1A to immunotherapy. Together, these findings suggest that blocking arachidonic acid metabolism can enhance immune responses against tumors by activating CD8+ T cells and inhibiting VM, which synergizes with ICIs to improve treatment of ARID1A-deficient CRC.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"212 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-05DOI: 10.1158/0008-5472.can-24-4553
Timothy Sears, Hannah Carter
Tumors utilize various mechanisms of HLA disruption in order to evade immune surveillance. Previous computational tools have interrogated specific aspects of this process, yet a holistic picture of HLA loss of heterozygosity (LOH), transcriptomic suppression, and alternative splicing has remained challenging. In a recent Nature Genetics study, Puttick and colleagues introduced MHC Hammer, a robust computational toolkit designed to dissect the complexities of HLA disruptions that mediate immune evasion in cancer. By analyzing comprehensive genomic and transcriptomic data across several large cancer cohorts, the study highlights the prevalence of HLA disruptions–particularly alternative splicing events–across various tumor types and identifies HLA LOH as an important immune evasion mechanism during metastasis in lung adenocarcinoma.
{"title":"MHC-Hammer decodes HLA disruption in tumors","authors":"Timothy Sears, Hannah Carter","doi":"10.1158/0008-5472.can-24-4553","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-4553","url":null,"abstract":"Tumors utilize various mechanisms of HLA disruption in order to evade immune surveillance. Previous computational tools have interrogated specific aspects of this process, yet a holistic picture of HLA loss of heterozygosity (LOH), transcriptomic suppression, and alternative splicing has remained challenging. In a recent Nature Genetics study, Puttick and colleagues introduced MHC Hammer, a robust computational toolkit designed to dissect the complexities of HLA disruptions that mediate immune evasion in cancer. By analyzing comprehensive genomic and transcriptomic data across several large cancer cohorts, the study highlights the prevalence of HLA disruptions–particularly alternative splicing events–across various tumor types and identifies HLA LOH as an important immune evasion mechanism during metastasis in lung adenocarcinoma.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"12 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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