Oncology
Abstract
Cancer immunotherapy has emerged as a promising therapeutic modality but heterogeneity in patient responsiveness remains. Thus, greater understanding of the immunologic factors that dictate response to immunotherapy is critical to improve patient outcomes. Here, we show that fibrinogen-like protein 2 (Fgl2) is elevated in the setting of melanoma in humans and mice and plays a functional role in inhibiting the CD8+ T cell response. Surprisingly, the tumor itself is not the major cellular source of Fgl2. Instead, we found that macrophage-secreted Fgl2 dampens the CD8+ T cell response through binding and apoptosis of FcγRIIB+CD8+ T cells. This regulation was CD8+ T cell autonomous and not via an antigen-presenting cell intermediary, as absence of Fcgr2b from the CD8+ T cells rendered T cells insensitive to Fgl2 regulation. Fgl2 is robustly expressed by macrophages in 10 cancer types in humans and in 6 syngeneic tumor models in mice, underscoring the clinical relevance of Fgl2 as a therapeutic target to promote T cell activity and improve patient immunotherapeutic response.
Authors
Kelsey B. Bennion, Julia Miranda R.Bazzano, Danya Liu, Maylene Wagener, Chrystal M. Paulos, Mandy L. Ford
Abstract
High-grade serous ovarian cancer (HGSOC) is the most prevalent and aggressive histological subtype of ovarian cancer and often presents with metastatic disease. The drivers of metastasis in HGSOC remain enigmatic. APOBEC3A (A3A), an enzyme that generates mutations across various cancers, has been proposed as a mediator of tumor heterogeneity and disease progression. However, the role of A3A in HGSOC has not been explored. We observed an association between high levels of APOBEC3-mediated mutagenesis and poor overall survival in primary HGSOC. We experimentally addressed this correlation by modeling A3A expression in HGSOC, and this resulted in increased metastatic behavior of HGSOC cells in culture and distant metastatic spread in vivo, which was dependent on catalytic activity of A3A. A3A activity in both primary and cultured HGSOC cells yielded consistent alterations in expression of epithelial-mesenchymal transition (EMT) genes resulting in hybrid EMT and mesenchymal signatures, providing a mechanism for their increased metastatic potential. Inhibition of key EMT factors TWIST1 and IL-6 resulted in mitigation of A3A-dependent metastatic phenotypes. Our findings define the prevalence of A3A mutagenesis in HGSOC and implicate A3A as a driver of HGSOC metastasis via EMT, underscoring its clinical relevance as a potential prognostic biomarker. Our study lays the groundwork for the development of targeted therapies aimed at mitigating the deleterious effect of A3A-driven EMT in HGSOC.
Authors
Jessica M. Devenport, Thi Tran, Brooke R. Harris, Dylan Fingerman, Rachel A. DeWeerd, Lojain H. Elkhidir, Danielle LaVigne, Katherine Fuh, Lulu Sun, Jeffrey J. Bednarski, Ronny Drapkin, Mary M. Mullen, Abby M. Green
Abstract
Glioblastoma (GBM) is the most lethal brain cancer, with GBM stem cells (GSCs) driving therapeutic resistance and recurrence. Targeting GSCs offers a promising strategy for preventing tumor relapse and improving outcomes. We identify SUV39H1, a histone-3, lysine-9 methyltransferase, as critical for GSC maintenance and GBM progression. SUV39H1 is upregulated in GBM compared with normal brain tissues, with single-cell RNA-seq showing its expression predominantly in GSCs due to super-enhancer–mediated activation. Knockdown of SUV39H1 in GSCs impaired their proliferation and stemness. Whole-cell RNA-seq analysis revealed that SUV39H1 regulates G2/M cell cycle progression, stem cell maintenance, and cell death pathways in GSCs. By integrating the RNA-seq data with ATAC-seq data, we further demonstrated that knockdown of SUV39H1 altered chromatin accessibility in key genes associated with these pathways. Chaetocin, an SUV39H1 inhibitor, mimics the effects of SUV39H1 knockdown, reducing GSC stemness and sensitizing cells to temozolomide, a standard GBM chemotherapy. In a patient-derived xenograft model, targeting SUV39H1 inhibits GSC-driven tumor growth. Clinically, high SUV39H1 expression correlates with poor glioma prognosis, supporting its relevance as a therapeutic target. This study identifies SUV39H1 as a crucial regulator of GSC maintenance and a promising therapeutic target to improve GBM treatment and patient outcomes.
Authors
Chunying Li, Qiqi Xie, Sugata Ghosh, Bihui Cao, Yuanning Du, Giau V. Vo, Timothy Y. Huang, Charles Spruck, Richard L. Carpenter, Y. Alan Wang, Q. Richard Lu, Kenneth P. Nephew, Jia Shen
Abstract
Many risk-eligible women refuse tamoxifen for primary prevention of breast cancer due to concerns about common side effects such as vasomotor symptoms. Tamoxifen may also induce or worsen insulin resistance and hypertriglyceridemia, especially in women with obesity. Bazedoxifene/conjugated estrogens (BZA/CE) reduces vasomotor symptoms and is currently undergoing evaluation for breast cancer risk reduction. However, the impact of BZA/CE on insulin resistance and metabolic health, particularly in those with excess adiposity, is understudied. Here, we examined the effects of obesity on response to BZA/CE in a rat model of breast cancer risk using older ovary-intact rats. Female Wistar rats received carcinogen to increase mammary cancer risk and were fed a high-fat diet to promote obesity. Lean and obese rats were selected based on adiposity, then randomized to BZA/CE or vehicle for 8 weeks. BZA/CE reduced adiposity, enriched small (insulin-sensitive) mammary adipocytes, increased the abundance of beneficial metabolic gut microbes (Faecalbaculum rodentium and Odoribacter laneus), and reversed obesity-associated changes in lipids and adipokines. BZA/CE also reversed obesity-induced mammary enrichment of cell proliferation pathways, consistent with risk-reducing effects. Together, these data support the use of BZA/CE to improve metabolic health and reduce breast cancer risk in individuals with obesity.
Authors
Erin D. Giles, Katherine L. Cook, Ramsey M. Jenschke, Karen A. Corleto, Danilo Landrock, Tara N. Mahmood, Katherine E. Sanchez, Alina Levin, Stephen D. Hursting, Bruce F. Kimler, Barry S. Komm, Carol J. Fabian
Abstract
The sentinel lymph node (SLN) is the first lymph node encountered by a metastatic cancer cell and serves as a predictor of poor prognosis, as patients with clinically occult SLN metastases are classified as stage III with elevated rates of recurrence and diminished overall survival. However, the dynamics of immune infiltrates in SLNs remain poorly characterized. Here, using an unbiased Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) technique, we profiled 97,777 cells from SLN tissues obtained from patients with stages I/II and III cutaneous melanoma. We describe the transcriptional programs of a multitude of T, B, and myeloid cell subtypes in SLNs. Based on the proportions of cell types, we determined that SLN subtypes are stratified along a naive → activated axis; patients with a ‘high activated’ signature score appear to be undergoing a robust melanoma antigen-driven adaptive immune response and thus, could be responsive to immunotherapy. Additionally, we identified transcriptomic signatures of SLN-infiltrating dendritic cell subsets that compromise anti-tumor immune responses. Our analyses provide valuable insights into tumor-driven immune changes in the SLN tissue, offering a powerful tool for the informed design of immune therapies for high-risk melanoma patients.
Authors
Eric Engelbrecht, Bryce F. Stamp, Lewis Chew, Omar Sadi Sarkar, Phillip Harter, Sabine J. Waigel, Eric C. Rouchka, Julia H. Chariker, Andrei Smolenkov, Jason A. Chesney, Kelly M. McMasters, Corey T. Watson, Kavitha Yaddanapudi
Abstract
While immune checkpoint inhibition (CPI) has reshaped cancer treatment, the majority of cancer patients do not benefit from this approach, which can also cause immune-related adverse events. Induction of IFNγ responses is thought be necessary for anti-tumor immunity, but growing evidence also implicates IFNγ as a tumor-intrinsic mediator of CPI resistance. CPI-induced IFNγ mediates activation-induced cell death in T cells as an immune-intrinsic mechanism of resistance. In this study, we show that transient block of IFNγ signaling through administration of the JAK1 inhibitor ABT-317 enhances anti-tumor T cell responses with CPI in pre-clinical models. Importantly, sequential but not concomitant ABT-317 treatment led to significantly reduced toxicity and improved tumor efficacy. Sequential treatment reduced activation-induced T cell death and enhanced expansion of tumor-reactive T cell subsets with increased effector function in vivo and ex vivo. Only CPI in combination with ABT-317 also enhanced memory responses by protecting mice from tumor rechallenge. These results demonstrate that JAK inhibition within a discrete time window following CPI addresses an immune-intrinsic mechanism of therapeutic resistance.
Authors
Marcel Arias-Badia, PeiXi Chen, Yee May Lwin, Aahir Srinath, Aram Lyu, Zenghua Fan, Serena S. Kwek, Diamond N. Luong, Ali Setayesh, Mason Sakamoto, Matthew Clark, Averey Lea, Rachel M. Wolters, Andrew Goodearl, Fiona A. Harding, Jacob V. Gorman, Wendy Ritacco, Lawrence Fong
Abstract
Lynch syndrome (LS), caused by inherited mutations in DNA mismatch repair genes including MSH2, carries a 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, mechanisms driving LS-associated EC remain unclear. We investigated MSH2 loss in EC pathogenesis using a mouse model (PR-Cre Msh2LoxP/LoxP, abbreviated Msh2KO), primary cell lines, human tissues, and human EC cells with isogenic MSH2 knockdown. By eight months, 58% of Msh2KO mice developed endometrial atypical hyperplasia (AH), a precancerous lesion. At 12-16 months, 47% of Msh2KO mice exhibited either AH or ECs with histologic similarities to human LS-ECs. Transcriptomic profiling of EC from Msh2KO mice revealed mitochondrial dysfunction-related pathway alterations. Subsequent studies in vitro and in vivo revealed mitochondrial dysfunction based upon two mechanisms: mitochondrial content reduction and structural disruptions in retained mitochondria. Human LS-ECs also exhibited mitochondrial content reduction compared to non-LS-ECs. Functional studies demonstrated metabolic reprogramming of MSH2-deficient EC cells, including reduced oxidative phosphorylation and increased susceptibility to glycolysis suppression. These findings identified mitochondrial dysfunction and metabolic disruption as consequences of MSH2 deficiency in EC. Mitochondrial and metabolic aberrations should be evaluated as biomarkers for endometrial carcinogenesis or risk stratification and represent potential targets for cancer interception in women with LS.
Authors
Mikayla Borthwick Bowen, Brenda Melendez, Qian Zhang, Diana Moreno, Leah Peralta, Wai-Kin Chan, Collene Jeter, Lin Tan, M. Anna Zal, Philip L. Lorenzi, Kenneth Dunner Jr., Richard K. Yang, Russell R. Broaddus, Joseph Celestino, Nisha Gokul, Elizabeth Whitley, Deena M. Scoville, Tae Hoon KIM, Jae-Wook Jeong, Rosemarie Schmandt, Karen Lu, Hyun-Eui Kim, Melinda S. Yates
Abstract
The omentum is the primary site of metastasis for ovarian cancer (OC). Interactions between cancer cells and adipocytes drive an invasive and pro-metastatic phenotype. Here we studied cancer cell-adipocyte crosstalk by using a direct co-culture model with immortalized human visceral pre-adipocytes (VNPAD) and OC cells. We demonstrate increased proliferation, invasiveness, and resistance to cisplatin of co-cultured compared to mono-cultured OC cells. RNA-sequencing of OC cells from co-culture vs. mono-culture revealed significant transcriptomic changes, identifying over 200 differentially expressed genes (DEGs) common to OVCAR5 and OVCAR8 cell lines. Enriched pathways included PI3K/AKT and Complement activation. Lipid transfer into OC cells from adipocytes induced upregulation of complement C3 and C5 proteins. Inhibiting C3 or C5 reversed the invasive phenotype and C3 knockdown reduced tumor progression in-vivo. Increased C3 expression was observed in omental implants compared to primary ovarian tumors and C3 secretion was higher in OC ascites from high BMI vs. low BMI patients. C3 upregulation in OC cells involved activation of ATF4-mediated integrated stress response (ISR). Overall, adipocyte-cancer cell interactions promote invasiveness and tumorigenesis via lipid transfer, activating ISR, and upregulating complement proteins C3 and C5.
Authors
Andres Valdivia, Ana Isac, Horacio Cardenas, Guangyuan Zhao, Yaqi Zhang, Hao Huang, Jian-Jun Wei, Mauricio Cuello-Fredes, Sumie Kato, Fernán Gómez-Valenzuela, Francoise A. Gourronc, Aloysius J. Klingelhutz, Daniela Matei
Abstract
Colorectal pre-cancers in Lynch Syndrome (LS) exhibit a distinct immune profile, presenting unique opportunities for developing immune-interception strategies to prevent carcinogenesis. Epigenetic modulation by EZH2 of immune-related genes is implicated in the carcinogenesis of different cancer types including colorectal. This study utilizes a mouse model of LS and ex vivo colonic organoids to assess the effects of the EZH2 inhibitor GSK503 on immune regulatory pathways, tumorigenesis, and epigenetic reprogramming. Our findings revealed that GSK503 significantly increased CD4+ and CD8+ T cells in both splenocytes and colonic mucosa of treated mice compared to controls. Additionally, a preventive dose of GSK503 over 9 weeks notably reduced adenoma multiplicity, demonstrating its efficacy as a preventive modality. Single-cell RNA sequencing and molecular analyses showed activation of immune and apoptotic markers, along with a reduction in H3K27 methylation levels in colonic crypts. ChIP sequencing further revealed decreased levels of H3K27me3 and H3K4me1, while levels of the active enhancer marks H3K4me3 and H3K27Ac increased in treated mice. Collectively, these findings indicate that EZH2 inhibition enhances immune responses through epigenetic reprogramming in the genome of LS mice, establishing a promising framework for the clinical development of EZH2 inhibitors as a cancer prevention strategy for LS carriers.
Authors
Charles M. Bowen, Fahriye Duzagac, Abel Martel-Martel, Laura Reyes-Uribe, Mahira Zaheer, Jacklyn Thompson, Nan Deng, Ria Sinha, Soham Mazumdar, Melissa W. Taggart, Abhinav K. Jain, Winfried Edelmann, Krishna M. Sinha, Eduardo Vilar
Abstract
BACKGROUND. 80% of patients with multiple endocrine neoplasia type 1 (MEN1) develop duodenopancreatic neuroendocrine tumors (dpNETs), of whom, 15% to 25% die of metastasis. There is a need to identify biomarkers to predict aggressive disease. MEN1 genotype affords an attractive possibility as a biomarker as it remains constant during lifetime. Currently, patients are clinically diagnosed with MEN1 by the presence of ≥ 2 primary endocrine tumors (pituitary, parathyroid and pancreas) or ≥ 1 primary endocrine tumor(s) with a positive family history. 10-30% of patients diagnosed clinically with MEN1 have no pathogenic germline MEN1 variants. METHODS. Retrospective study of 162 index patients or probands with genotype-positive and 47 with genotype-negative MEN1 enrolled from 1977–2022. RESULTS. Compared to patients with genotype-negative disease, patients with genotype-positive disease were younger at diagnosis and had an increased frequency of recurrent parathyroid tumors, dpNETs and angiofibromas or collagenomas. We propose a novel weighted scoring system to diagnose genotype-positive MEN1 based on clinical characteristics. No evidence of MEN1 mosaicism was seen in 30 tumors from 17 patients with genotype-negative MEN1. Patients with germline MEN1 variants in exons 2 and 3 have a reduced risk of distant metastases. CONCLUSIONS. The clinical course of genotype-negative MEN1 is distinct from genotype-positive disease raising uncertainty about the benefits of lifetime surveillance inpatients with genotype-negative disease. MEN1 mosaicism is rare. TRIAL REGISTRATION. ClinicalTrials.gov NCT04969926. FUNDING. Intramural Research Program of NIDDK (ZIA DK043006-46).
Authors
Charlita C. Worthy, Rana Tora, Chandra N. Uttarkar, James M. Welch, Lynn Bliss, Craig Cochran, Anisha Ninan, Sheila Kumar, Stephen Wank, Sungyoung Auh, Lee S. Weinstein, William F. Simonds, Sunita K. Agarwal, Jenny E. Blau, Smita Jha
No posts were found with this tag.
