Oncology
Abstract
The androgen receptor (AR) is a master transcription factor that regulates prostate cancer (PC) development and progression. Inhibition of AR signaling by androgen deprivation is the first-line therapy with initial efficacy for advanced and recurrent PC. Paradoxically, supraphysiological levels of testosterone (SPT) also inhibit PC progression. However, as with any therapy, not all patients show a therapeutic benefit, and responses differ widely in magnitude and duration. In this study, we evaluated whether differences in the AR cistrome before treatment can distinguish between SPT-responding (R) and -nonresponding (NR) tumors. We provide the first preclinical evidence to our knowledge that SPT-R tumors exhibit a distinct AR cistrome when compared with SPT-NR tumors, indicating a differential biological role of the AR. We applied an integrated analysis of ChIP-Seq and RNA-Seq to the pretreatment tumors and identified an SPT-R signature that distinguishes R and NR tumors. Because transcriptomes of SPT-treated clinical specimens are not available, we interrogated available castration-resistant PC (CRPC) transcriptomes and showed that the SPT-R signature is associated with improved survival and has the potential to identify patients who would respond to SPT. These findings provide an opportunity to identify the subset of patients with CRPC who would benefit from SPT therapy.
Authors
Xintao Qiu, Lisha G. Brown, Jennifer L. Conner, Holly M. Nguyen, Nadia Boufaied, Sarah Abou Alaiwi, Ji-Heui Seo, Talal El Zarif, Connor Bell, Edward O’Connor, Brian Hanratty, Mark Pomerantz, Matthew L. Freedman, Myles Brown, Michael C. Haffner, Peter S. Nelson, Felix Y. Feng, David P. Labbé, Henry W. Long, Eva Corey
Abstract
Cyclophosphamide (CPA) and doxorubicin (DOX) are key components of chemotherapy for triple-negative breast cancer (TNBC) although suboptimal outcomes are commonly associated with drug resistance and/or intolerable side-effects. Through an approach combining high-throughput screening and chemical modification, we developed CN06 as a dual activator of the constitutive androstane receptor (CAR) and nuclear factor erythroid 2-related factor 2 (Nrf2). CN06 enhances CAR-induced bioactivation of CPA (a prodrug) by provoking hepatic expression of CYP2B6, while repressing DOX-induced cytotoxicity in cardiomyocytes in vitro via stimulating Nrf2-antioxidant signaling. Utilizing a multicellular co-culture model incorporating human primary hepatocytes, TNBC cells, and cardiomyocytes, we show that CN06 increased CPA/DOX-mediated TNBC cell death via CAR-dependent CYP2B6 induction and subsequent conversion of CPA to its active metabolite 4-hydroxy-CPA, while protecting against DOX-induced cardiotoxicity by selectively activating Nrf2-antioxidant signaling in cardiomyocytes but not in TNBC cells. Further, CN06 preserves the viability and function of human iPSC-derived cardiomyocytes by modulating antioxidant defenses, decreasing apoptosis, and enhancing the kinetics of contraction and relaxation. Collectively, our findings identify CAR and Nrf2 as novel combined therapeutic targets whereby CN06 holds the potential to improve the efficacy:toxicity ratio of CPA/DOX-containing chemotherapy.
Authors
Sydney Stern, Dongdong Liang, Linhao Li, Ritika Kurian, Caitlin Lynch, Srilatha Sakamuru, Scott Heyward, Junran Zhang, Kafayat Ajoke Kareem, Young Wook Chun, Ruili Huang, Menghang Xia, Charles C. Hong, Fengtian Xue, Hongbing Wang
Abstract
Tertiary lymphoid structures (TLSs) are transient ectopic lymphoid aggregates whose formation might be caused by chronic inflammation states, such as cancer. However, how TLSs are induced in the tumor microenvironment (TME) and how they affect patient survival are not well understood. We investigated TLS distribution in relation to tumor infiltrating lymphocytes (TILs) and related gene expression in high grade serous ovarian cancer (HGSC) specimens. CXCL13 gene expression correlated with TLS presence and the infiltration of T cells and B cells, and was a favorable prognostic factor for HGSC patients. Coexistence of CD8+ T cells and B-cell lineages in the TME significantly improved the prognosis of HGSC and was correlated with the presence of TLSs. CXCL13 expression was predominantly coincident with CD4+ T cells in TLSs and CD8+ T cells in TILs, and shifted from CD4+ T cells to CD21+ follicular dendritic cells as TLS matured. In a mouse ovarian cancer model, recombinant CXCL13 induced TLSs and enhanced survival by the infiltration of CD8+ T cells. These results suggest that TLS formation was associated with CXCL13-producing CD4+ T cells and that TLSs facilitated the coordinated antitumor response of cellular and humoral immunity in ovarian cancer.
Authors
Masayo Ukita, Junzo Hamanishi, Hiroyuki Yoshitomi, Koji Yamanoi, Shiro Takamatsu, Akihiko Ueda, Haruka Suzuki, Yuko Hosoe, Yoko Furutake, Mana Taki, Kaoru Abiko, Ken Yamaguchi, Hidekatsu Nakai, Tsukasa Baba, Noriomi Matsumura, Akihiko Yoshizawa, Hideki Ueno, Masaki Mandai
Abstract
Rearrangements that drive ectopic MEF2C expression have recurrently been found in human early thymocyte progenitor acute lymphoblastic leukemia (ETP-ALL) patients. Here we show high levels of MEF2C expression in ETP-ALL patients. Using both in vivo and in vitro models of ETP-ALL, we demonstrate that elevated MEF2C expression blocks NOTCH-induced T cell differentiation while promoting a B-lineage program. MEF2C activates a B cell transcriptional program in addition to RUNX1, GATA3 and LMO2, upregulates the IL7R and boosts cell survival by upregulation of BCL2. MEF2C and the Notch pathway therefore demarcate opposite regulators of B- or T-lineage choices, respectively. Enforced MEF2C expression in mouse or human progenitor cells effectively blocks early T cell differentiation and promotes the development of bi-phenotypic lymphoid tumors that co-express CD3 and CD19, resembling human mixed phenotype acute leukemia (MPAL). SIK inhibitors impair MEF2C activity and alleviate the T cell development block. Importantly, this sensitizes cells to prednisolone treatment. Therefore, SIK inhibiting compounds such as dasatinib are potentially a valuable addition to standard chemotherapy for human ETP-ALL.
Authors
Kirsten Canté-Barrett, Mariska T. Meijer, Valentina Cordo', Rico Hagelaar, Wentao Yang, Jiyang Yu, Willem K. Smits, Marloes E. Nulle, Joris P. Jansen, Rob Pieters, Jun J. Yang, Jody J. Haigh, Steven Goossens, Jules P.P. Meijerink
Abstract
Recent studies highlighted the clinicopathologic importance of tumor microenvironment (TME) in delineating molecular attributes and therapeutic potentials. However, the overall TME cell-infiltration landscape in non-squamous NSCLC have not been comprehensively recognized. In this study, we employed consensus non-negative matrix factorization (NMF) molecular subtyping to determine the TME cell infiltration patterns and identified three TME clusters (TME-C1, -C2, -C3) characterized by distinct clinicopathologic features, infiltrating cells, and biological processes. Proteomics analyses revealed that cGAS-STING immune signaling mediated protein and phosphorylation level were significantly upregulated in inflamed-related TME-C2 clusters. The TMEsig-score extracted from the TME-related signature divided NSCLC patients into high- and low-score subgroups, where a high score was associated with favorable prognosis and immune infiltration. Genomic landscape revealed that patients with low TMEsig-score harbored greater somatic copy number alternations and higher mutation frequency of driver genes involving STK11, KEAP1 and SMARCA4 et al. Drug sensitivity analyses suggested that tumors with high TMEsig-score were responsible for favorable clinical response to immune check-point inhibitors (ICI) treatment. In summary, this study highlights that comprehensive recognizing of the TME cell infiltration landscape will contribute to enhance our understanding of TME immune regulation and promote effectiveness of precision biotherapy strategies.
Authors
Hao Chen, Tongchao Zhang, Yuan Zhang, Hao Wu, Zhen Fang, Yang Liu, Yang Chen, Zhe Wang, Shengtao Jia, Xingzhao Ji, Liang Shang, Fengying Du, Jin Liu, Ming Lu, Wei Chong
Abstract
DNA damage and genomic instability contribute to non-small cell lung cancer (NSCLC) etiology and progression. However, their therapeutic exploitation is disappointing. CTC-derived eXplants (CDX) offer systems for mechanistic investigation of CTC metastatic potency and may provide rationale for biology-driven therapeutics. Four CDX models and three CDX-derived cell lines were established from NSCLC CTCs and recapitulated patient tumor histology and response to platinum-based chemotherapy. CDX (GR-CDXL1, GR-CDXL2, GR-CDXL3, GR-CDXL4) demonstrated considerable mutational landscape similarity with patient tumor biopsy and/or single CTCs. Truncal alterations in key DNA damage response (DDR) and genome integrity-related genes were prevalent across models and assessed as therapeutic targets in vitro, in ovo and in vivo. GR-CDXL1 presented homologous recombination deficiency linked to bi-allelic BRCA2 mutation and FANCA deletion, unrepaired DNA lesions post-mitosis and olaparib sensitivity, despite resistance to chemotherapy. SLFN11 overexpression in GR-CDXL4 led to olaparib sensitivity and was in coherence with neuroendocrine marker expression in patient tumor biopsy, suggesting a predictive value of SLFN11 in NSCLC histological transformation into SCLC. Centrosome clustering promoted targetable chromosomal instability in GR-CDXL3 cells. These CDX unravel DDR and genome integrity-related defects as a central mechanism underpinning metastatic potency of CTCs and provide rationale for their therapeutic targeting in metastatic NSCLC.
Authors
Tala Tayoun, Vincent Faugeroux, Marianne Oulhen, Olivier Déas, Judith Michels, Laura Brulle-Soumare, Stefano Cairo, Jean-Yves Scoazec, Virginie Marty, Agathe Aberlenc, David Planchard, Jordi Remon, Santiago Ponce, Benjamin Besse, Patricia L. Kannouche, Jean-Gabriel Judde, Patrycja Pawlikowska, Françoise Farace
Abstract
In many solid cancers, tumor-associated macrophages (TAM) represent the predominant myeloid cell population. Antigen (Ag) cross-presentation leading to tumor Ag-directed cytotoxic CD8+ T cell responses is crucial for anti-tumor immunity. However, the role of recruited monocyte-derived macrophages, including TAM, as potential cross-presenting cells is not well understood. Here, we show that primary human as well as mouse CD206+ macrophages are effective in functional cross-presentation of soluble self and non-self Ag, including tumor-associated Ag (TAA) as well as viral Ag. To confirm the presence of cross-presenting TAM in vivo, we performed phenotypic and functional analysis of TAM from B16-F10 and CT26 syngeneic tumor models and have identified CD11b+F4/80hiCD206+ TAM to effectively cross-present TAA. We show that CD11b+CD206+ TAM represent the dominant tumor-infiltrating myeloid cell population, expressing a unique cell surface repertoire, promoting Ag cross-presentation and Ag-specific CD8+ T cell activation comparable to cross-presenting CLEC9A+ dendritic cells (cDC1). The presence of cross-presenting CD206+ TAM is associated with reduced tumor burden in mouse syngeneic tumor models and with improved overall survival in cutaneous melanoma patients. Therefore, the demonstration of effective Ag cross-presentation capabilities of CD206+ TAM, including their clinical relevance, expands our understanding of TAM phenotypic diversity and functional versatility.
Authors
Madhura Modak, Ann-Kathrin Mattes, Daniela Reiss, Wioletta Skronska-Wasek, Rebecca Langlois, Nicolas Sabarth, Renate Konopitzky, Fidel Ramírez, Katharina Lehr, Tobias Mayr, David Kind, Coralie Viollet, Lee Kim Swee, Jutta Petschenka, Karim Christian El Kasmi, Elfriede Noessner, Kerstin Kitt, Stefan Pflanz
Abstract
Insight into processes that determine CD8+ T cell memory formation has been obtained from infection models. These models are biased toward an inflammatory milieu and often employ high avidity CD8+ T cells in adoptive transfer procedures. It is unclear whether these conditions mimic the differentiation processes of an endogenous repertoire that proceed upon non-inflammatory conditions prevailing in premalignant tumor lesions. We examined the role of cytolytic capacity on CD8+ T cell fate decisions when primed by tumor cells or by minor histocompatibility antigen-mismatched leukocytes. CD8+ memory commitment was analyzed in Ebag9-deficient mice that exhibit an enhanced tumor cell lysis. This property endowed Ebag9-/- mice with extended control of Tcl-1 oncogene-induced chronic lymphocytic leukemia progression. In Ebag9-/- mice, an expanded memory population was obtained for anti-HY and anti-SV40 T antigen-specific T cells, despite unchanged effector frequencies in the primary response. By comparing the single-cell transcriptomes of CD8+ T cells responding to tumor cell vaccination, we found differential distribution of subpopulations between Ebag9+/+ and Ebag9-/- T cells. In Ebag9-/- cells, these larger clusters contained genes encoding transcription factors regulating memory cell differentiation, along with anti-apoptotic gene functions. Our findings link EBAG9-controlled cytolytic activity and the commitment to the CD8+ memory lineage.
Authors
Armin Rehm, Anthea Wirges, Dana Hoser, Cornelius Fischer, Stefanie Herda, Kerstin Gerlach, Sascha Sauer, Gerald Willimsky, Uta E. Höpken
Abstract
BACKGROUND. Fibrolamellar carcinoma (FLC) is an aggressive liver cancer primarily afflicting adolescents and young adults. Patients with FLC harbor a heterozygous deletion on chromosome 19 that leads to the oncogenic gene fusion, DNAJB1-PRKACA. There are currently no effective therapeutics for FLC. To work toward that end, it is critical to gain deeper mechanistic insight into FLC pathogenesis. METHODS. We assembled a large sample set of FLC and non-malignant liver tissue (n=52) and performed integrative multi-omic analysis. Specifically, we carried out small RNA-sequencing to define altered microRNA expression patterns in tumor samples and then coupled this analysis with RNA sequencing (RNA-seq) and chromatin run-on sequencing (ChRO-seq) data to identify candidate master microRNA regulators of gene expression in FLC. We also evaluated the relationship between DNAJB1-PRKACA and microRNAs of interest in several human and mouse cell models. Finally, we performed loss-of-function experiments for a specific microRNA in cells established from a patient-derived xenograft (PDX) model. RESULTS. We identified miR-10b-5p and miR-455-3p as the top candidate pro-proliferative and tumor suppressive microRNAs, respectively. In multiple human cell models, but not in mouse cell models, over-expression of DNAJB1-PRKACA leads to significant up-regulation of miR-10b-5p. In cells established from a PDX model, inhibition of miR-10b increases the expression of several novel target genes, including the anti-proliferative factors TRIM35 and SUN2, concomitant with a significant reduction in metabolic activity, anchorage-independent growth, and proliferation. CONCLUSION. This functional genomics study highlights a novel proliferative axis in FLC and provides a rich resource for further investigation of the molecular landscape of FLC. The results reveal that miR-10b-5p shapes gene expression and promotes cell proliferation in FLC. Future studies are necessary to identify how the loss of miR-455-3p contributes to FLC progression and how miR-10b-5p may coordinate with miR-455-3p to control tumor phenotypes.
Authors
Adam B. Francisco, Matt Kanke, Andrew P. Massa, Timothy A. Dinh, Ramja Sritharan, Khashayar Vakili, Nabeel Bardeesy, Praveen Sethupathy
Abstract
K-ras mutant lung adenocarcinoma (KM-LUAD) is associated with abysmal prognosis and tightly linked to tumor-promoting inflammation. A human monoclonal antibody targeting proinflammatory cytokine IL-1β, Canakinumab, was found to significantly decrease the risk of lung cancer in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study. Interestingly, we found high levels of IL-1β in the lungs of mice with K-rasG12D mutant tumors (CC-LR). Here we blocked IL-1β using a monoclonal anti-IL-1β antibody in cohorts of 6 or 14-week-old CC-LR mice to explore its preventive and therapeutic effect, respectively. IL-1β blockade significantly reduced lung tumor burden, which was associated with reprogramming of the lung microenvironment toward an anti-tumor phenotype characterized by increased infiltration of cytotoxic CD8+ T cells (with high IFN-γ and granzyme B but low PD-1 expression) while suppressing neutrophil and polymorphonuclear myeloid-derived suppressor cell responses. In querying the TCGA dataset, we interestingly found positive correlations between IL1B expression and infiltration of immunosuppressive polymorphonuclear cells and expression of their chemoattractant, CXCL1, and PDCD1 expressions in patients with KM-LUAD. Our data provide evidence that IL-1β blockade may serve as a preventive strategy among high-risk individuals and an alternative therapeutic approach in combination with currently available treatments for KM-LUAD.
Authors
Bo Yuan, Michael J. Clowers, Walter V. Velasco, Stephen Peng, Qian Peng, Yewen Shi, Marco Ramos-Castaneda, Melody Zarghooni, Shuanying Yang, Rachel L. Babcock, Seon Hee Chang, John V. Heymach, Jianjun Zhang, Edwin J. Ostrin, Stephanie S. Watowich, Humam Kadara, Seyed Javad Moghaddam
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