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Single-cell analysis of localized prostate cancer patients links high Gleason score with an immunosuppressive profile

Adorno Febles, Victor R; Hao, Yuan; Ahsan, Aarif; Wu, Jiansheng; Qian, Yingzhi; Zhong, Hua; Loeb, Stacy; Makarov, Danil V; Lepor, Herbert; Wysock, James; Taneja, Samir S; Huang, William C; Becker, Daniel J; Balar, Arjun V; Melamed, Jonathan; Deng, Fang-Ming; Ren, Qinghu; Kufe, Donald; Wong, Kwok-Kin; Adeegbe, Dennis O; Deng, Jiehui; Wise, David R
BACKGROUND:Evading immune surveillance is a hallmark for the development of multiple cancer types. Whether immune evasion contributes to the pathogenesis of high-grade prostate cancer (HGPCa) remains an area of active inquiry. METHODS:Through single-cell RNA sequencing and multicolor flow cytometry of freshly isolated prostatectomy specimens and matched peripheral blood, we aimed to characterize the tumor immune microenvironment (TME) of localized prostate cancer (PCa), including HGPCa and low-grade prostate cancer (LGPCa). RESULTS: TILs. The PCa TME was infiltrated by macrophages but these did not clearly cluster by M1 and M2 markers. CONCLUSIONS:T cell exhaustion in localized PCa, a finding enriched in HGPCa relative to LGPCa. These studies suggest a possible link between the clinical-pathologic risk of PCa and the associated TME. Our results have implications for our understanding of the immunologic mechanisms of PCa pathogenesis and the implementation of immunotherapy for localized PCa.
PMID: 36988342
ISSN: 1097-0045
CID: 5463282

Histone Deacetylase 6 Inhibition Exploits Selective Metabolic Vulnerabilities in LKB1 Mutant, KRAS Driven NSCLC

Zhang, Hua; Nabel, Christopher S; Li, Dezhi; O'Connor, Ruth Í; Crosby, Caroline R; Chang, Sarah M; Hao, Yuan; Stanley, Robyn; Sahu, Soumyadip; Levin, Daniel S; Chen, Ting; Tang, Sittinon; Huang, Hsin-Yi; Meynardie, Mary; Stephens, Janaye; Sherman, Fiona; Chafitz, Alison; Costelloe, Naoise; Rodrigues, Daniel A; Fogarty, Hilda; Kiernan, Miranda G; Cronin, Fiona; Papadopoulos, Eleni; Ploszaj, Magdalena; Weerasekara, Vajira; Deng, Jiehui; Kiely, Patrick; Bardeesy, Nabeel; Vander Heiden, Matthew G; Chonghaile, Triona Ni; Dowling, Catríona M; Wong, Kwok-Kin
INTRODUCTION/BACKGROUND:In KRAS-mutant NSCLC, co-occurring alterations in LKB1 confer a negative prognosis compared with other mutations such as TP53. LKB1 is a tumor suppressor that coordinates several signaling pathways in response to energetic stress. Our recent work on pharmacologic and genetic inhibition of histone deacetylase 6 (HDAC6) revealed the impaired activity of numerous enzymes involved in glycolysis. On the basis of these previous findings, we explored the therapeutic window for HDAC6 inhibition in metabolically-active KRAS-mutant lung tumors. METHODS:Using cell lines derived from mouse autochthonous tumors bearing the KRAS/LKB1 (KL) and KRAS/TP53 mutant genotypes to control for confounding germline and somatic mutations in human models, we characterize the metabolic phenotypes at baseline and in response to HDAC6 inhibition. The impact of HDAC6 inhibition was measured on cancer cell growth in vitro and on tumor growth in vivo. RESULTS:Surprisingly, KL-mutant cells revealed reduced levels of redox-sensitive cofactors at baseline. This is associated with increased sensitivity to pharmacologic HDAC6 inhibition with ACY-1215 and blunted ability to increase compensatory metabolism and buffer oxidative stress. Seeking synergistic metabolic combination treatments, we found enhanced cell killing and antitumor efficacy with glutaminase inhibition in KL lung cancer models in vitro and in vivo. CONCLUSIONS:Exploring the differential metabolism of KL and KRAS/TP53-mutant NSCLC, we identified decreased metabolic reserve in KL-mutant tumors. HDAC6 inhibition exploited a therapeutic window in KL NSCLC on the basis of a diminished ability to compensate for impaired glycolysis, nominating a novel strategy for the treatment of KRAS-mutant NSCLC with co-occurring LKB1 mutations.
PMID: 36958689
ISSN: 1556-1380
CID: 5462882

DNA methylation profiling identifies subgroups of lung adenocarcinoma with distinct immune cell composition, DNA methylation age, and clinical outcome

Guidry, Kayla; Vasudevaraja, Varshini; Labbe, Kristen; Mohamed, Hussein; Serrano, Jonathan; Guidry, Brett W; DeLorenzo, Michael; Zhang, Hua; Deng, Jiehui; Sahu, Soumyadip; Almonte, Christina; Moreira, Andre L; Tsirigos, Aristotelis; Papagiannakopoulos, Thales; Pass, Harvey; Snuderl, Matija; Wong, Kwok-Kin
PURPOSE/OBJECTIVE:Lung adenocarcinoma (LUAD) is a clinically heterogenous disease, which is highlighted by the unpredictable recurrence in low-stage tumors and highly variable responses observed in patients treated with immunotherapies, which cannot be explained by mutational profiles. DNA methylation-based classification and understanding of microenviromental heterogeneity may allow stratification into clinically relevant molecular subtypes of LUADs. EXPERIMENTAL DESIGN/METHODS:We characterize the genome-wide DNA methylation landscape of 88 resected LUAD tumors. Exome sequencing focusing on a panel of cancer-related genes was used to genotype these adenocarcinoma samples. Bioinformatic and statistical tools, the immune cell composition, DNA methylation age (DNAm age), and DNA methylation clustering were used to identify clinically relevant subgroups. RESULTS:Deconvolution of DNA methylation data identified immunologically hot and cold subsets of lung adenocarcinomas. Additionally, concurrent factors were analyzed that could affect the immune microenvironment, such as smoking history, ethnicity, or presence of KRAS or TP53 mutations. When the DNAm age was calculated, a lower DNAm age was correlated with the presence of a set of oncogenic drivers, poor overall survival, and specific immune cell populations. Unsupervised DNA methylation clustering identified 6 molecular subgroups of LUAD tumors with distinct clinical and microenvironmental characteristics. CONCLUSIONS:Our results demonstrate that DNA methylation signatures can stratify lung adenocarcinoma into clinically relevant subtypes, and thus such classification of LUAD at the time of resection may lead to better methods in predicting tumor recurrence and therapy responses.
PMID: 35802677
ISSN: 1557-3265
CID: 5280672

Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

Chang, Chewei Anderson; Jen, Jayu; Jiang, Shaowen; Sayad, Azin; Mer, Arvind Singh; Brown, Kevin R; Nixon, Allison M L; Dhabaria, Avantika; Tang, Kwan Ho; Venet, David; Sotiriou, Christos; Deng, Jiehui; Wong, Kwok-Kin; Adams, Sylvia; Meyn, Peter; Heguy, Adriana; Skok, Jane A; Tsirigos, Aristotelis; Ueberheide, Beatrix; Moffat, Jason; Singh, Abhyudai; Haibe-Kains, Benjamin; Khodadadi-Jamayran, Alireza; Neel, Benjamin G
Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. "Drug-tolerant persisters" (DTPs), a sub-population of cancer cells that survive via reversible, non-genetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKIs) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single cell RNA-sequencing reveal that HER2+ breast cancer cells cycle stochastically through a "pre-DTP" state, characterized by a G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting show that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2+ breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor-dependent induction of SGK3, leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation.
PMID: 34911733
ISSN: 2159-8290
CID: 5085072

Loss of TSC1/TSC2 sensitizes immune checkpoint blockade in non-small cell lung cancer

Huang, Qingyuan; Li, Fei; Hu, Hai; Fang, Zhaoyuan; Gao, Zhendong; Xia, Guozhan; Ng, Wai-Lung; Khodadadi-Jamayran, Alireza; Chen, Ting; Deng, Jiehui; Zhang, Hua; Almonte, Christina; Labbe, Kristen; Han, Han; Geng, Ke; Tang, Sittinon; Freeman, Gordon J; Li, Yuan; Chen, Haiquan; Wong, Kwok-Kin
Tuberous sclerosis complex subunit 1 (TSC1) and 2 (TSC2) are frequently mutated in non-small cell lung cancer (NSCLC), however, their effects on antitumor immunity remained unexplored. A CRISPR screening in murine KrasG12D
PMID: 35119931
ISSN: 2375-2548
CID: 5150752

Targeting the Atf7ip-Setdb1 Complex Augments Antitumor Immunity by Boosting Tumor Immunogenicity

Hu, Hai; Khodadadi-Jamayran, Alireza; Dolgalev, Igor; Cho, Hyunwoo; Badri, Sana; Chiriboga, Luis A; Zeck, Briana; Lopez De Rodas Gregorio, Miguel; Dowling, Catríona M; Labbe, Kristen; Deng, Jiehui; Chen, Ting; Zhang, Hua; Zappile, Paul; Chen, Ze; Ueberheide, Beatrix; Karatza, Angeliki; Han, Han; Ranieri, Michela; Tang, Sittinon; Jour, George; Osman, Iman; Sucker, Antje; Schadendorf, Dirk; Tsirigos, Aristotelis; Schalper, Kurt A; Velcheti, Vamsidhar; Huang, Hsin-Yi; Jin, Yujuan; Ji, Hongbin; Poirier, John T; Li, Fei; Wong, Kwok-Kin
Substantial progress has been made in understanding how tumors escape immune surveillance. However, few measures to counteract tumor immune evasion have been developed. Suppression of tumor antigen expression is a common adaptive mechanism that cancers use to evade detection and destruction by the immune system. Epigenetic modifications play a critical role in various aspects of immune invasion, including the regulation of tumor antigen expression. To identify epigenetic regulators of tumor antigen expression, we established a transplantable syngeneic tumor model of immune escape with silenced antigen expression and used this system as a platform for a CRISPR-Cas9 suppressor screen for genes encoding epigenetic modifiers. We found that disruption of the genes encoding either of the chromatin modifiers activating transcription factor 7-interacting protein (Atf7ip) or its interacting partner SET domain bifurcated histone lysine methyltransferase 1 (Setdb1) in tumor cells restored tumor antigen expression. This resulted in augmented tumor immunogenicity concomitant with elevated endogenous retroviral (ERV) antigens and mRNA intron retention. ERV disinhibition was associated with a robust type I interferon response and increased T-cell infiltration, leading to rejection of cells lacking intact Atf7ip or Setdb1. ATF7IP or SETDB1 expression inversely correlated with antigen processing and presentation pathways, interferon signaling, and T-cell infiltration and cytotoxicity in human cancers. Our results provide a rationale for targeting Atf7ip or Setdb1 in cancer immunotherapy.
PMID: 34462284
ISSN: 2326-6074
CID: 5061142

Targeting HER2 Exon 20 Insertion-Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib

Han, Han; Li, Shuai; Chen, Ting; Fitzgerald, Michael; Liu, Shengwu; Peng, Chengwei; Tang, Kwan Ho; Cao, Shougen; Chouitar, Johara; Wu, Jiansheng; Peng, David; Deng, Jiehui; Gao, Zhendong; Baker, Theresa E; Li, Fei; Zhang, Hua; Pan, Yuanwang; Ding, Hailin; Hu, Hai; Pyon, Val; Thakurdin, Cassandra; Papadopoulos, Eleni; Tang, Sittinon; Gonzalvez, Francois; Chen, Haiquan; Rivera, Victor M; Brake, Rachael; Vincent, Sylvie; Wong, Kwok-Kin
No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion-mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion-mutant lung adenocarcinoma patients. SIGNIFICANCE: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion-mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.
PMID: 34380634
ISSN: 1538-7445
CID: 5060992

The KRASG12C Inhibitor MRTX849 Reconditions the Tumor Immune Microenvironment and Sensitizes Tumors to Checkpoint Inhibitor Therapy

Briere, David M; Li, Shuai; Calinisan, Andrew; Sudhakar, Niranjan; Aranda, Ruth; Hargis, Lauren; Peng, David H; Deng, Jiehui; Engstrom, Lars D; Hallin, Jill; Gatto, Sole; Fernandez-Banet, Julio; Pavlicek, Adam; Wong, Kwok-Kin; Christensen, James G; Olson, Peter
KRASG12C inhibitors, including MRTX849, are promising treatment options for KRAS-mutant non-small cell lung cancer (NSCLC). PD-1 inhibitors are approved in NSCLC; however, strategies to enhance checkpoint inhibitor therapy (CIT) are needed. KRASG12C mutations are smoking-associated transversion mutations associated with high tumor mutation burden (TMB), PD-L1 positivity and an immunosuppressive tumor microenvironment. To evaluate the potential of MRTX849 to augment CIT, its impact on immune signaling and response to CIT was evaluated. In human tumor xenograft models, MRTX849 increased MHC class I protein expression and decreased RNA and/or plasma protein levels of immunosuppressive factors. In a KRASG12C-mutant CT26 syngeneic mouse model, MRTX849 decreased intratumoral myeloid-derived suppressor cells (MDSCs) and increased M1-polarized macrophages, dendritic cells, CD4+ and CD8+ T cells. Similar results were observed in lung KrasG12C-mutant syngeneic and a genetically engineered mouse (GEM) model. In the CT26 KrasG12C model, MRTX849 demonstrated marked tumor regression when tumors were established in immune-competent BALB/c mice; however, the effect was diminished when tumors were grown in T-cell deficient nu/nu mice. Tumors progressed following anti-PD-1 or MRTX849 single agent treatment in immune-competent mice; however, combination treatment demonstrated durable, complete responses (CRs). Tumors did not re-establish in the same mice that exhibited durable CRs when re-challenged with tumor cell inoculum, demonstrating these mice developed adaptive anti-tumor immunity. In a GEM model, treatment with MRTX849 plus anti-PD-1 led to increased progression-free survival compared to either single agent alone. These data demonstrate KRAS inhibition reverses an immunosuppressive tumor microenvironment and sensitizes tumors to CIT through multiple mechanisms.
PMID: 33722854
ISSN: 1538-8514
CID: 4837732

ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1 mutant lung cancer

Deng, Jiehui; Thennavan, Aatish; Dolgalev, Igor; Chen, Ting; Li, Jie; Marzio, Antonio; Poirier, John T; Peng, David; Bulatovic, Mirna; Mukhopadhyay, Subhadip; Silver, Heather; Papadopoulos, Eleni; Pyon, Val; Thakurdin, Cassandra; Han, Han; Li, Fei; Li, Shuai; Ding, Hailin; Hu, Hai; Pan, Yuanwang; Weerasekara, Vajira; Jiang, Baishan; Wang, Eric S; Ahearn, Ian; Philips, Mark; Papagiannakopoulos, Thales; Tsirigos, Aristotelis; Rothenberg, Eli; Gainor, Justin; Freeman, Gordon J; Rudin, Charles M; Gray, Nathanael S; Hammerman, Peter S; Pagano, Michele; Heymach, John V; Perou, Charles M; Bardeesy, Nabeel; Wong, Kwok-Kin
PMID: 34142094
ISSN: 2662-1347
CID: 4917722

SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling

Fedele, Carmine; Li, Shuai; Teng, Kai Wen; Foster, Connor J R; Peng, David; Ran, Hao; Mita, Paolo; Geer, Mitchell J; Hattori, Takamitsu; Koide, Akiko; Wang, Yubao; Tang, Kwan Ho; Leinwand, Joshua; Wang, Wei; Diskin, Brian; Deng, Jiehui; Chen, Ting; Dolgalev, Igor; Ozerdem, Ugur; Miller, George; Koide, Shohei; Wong, Kwok-Kin; Neel, Benjamin G
KRAS is the most frequently mutated human oncogene, and KRAS inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP and react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C activation and inhibitor engagement, we found that an SHP2 inhibitor (SHP2-I) increases KRAS-GDP occupancy, enhancing G12C-I efficacy. The SHP2-I abrogated RTK feedback signaling and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). SHP2-I/G12C-I combination evoked favorable but tumor site-specific changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using cells expressing inhibitor-resistant SHP2 showed that SHP2 inhibition in PDAC cells is required for PDAC regression and remodeling of the immune microenvironment but revealed direct inhibitory effects on tumor angiogenesis and vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies.
PMID: 33045063
ISSN: 1540-9538
CID: 4632492