Excellence in Science

Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression

How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissuespecific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-triphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination- mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.

Qingsong Hu, Youqiong Ye, Li-Chuan Chan , Yajuan Li, Ke Liang, Aifu Lin, Sergey D. Egranov, Yaohua Zhang, Weiya Xia, Jing Gong, Yinghong Pan, Sujash S. Chatterjee, Jun Yao , Kurt W. Evans, Tina K. Nguyen, Peter K. Park, Jiewei Liu, Cristian Coarfa, Sri Ramya Donepudi, Vasanta Putluri, Nagireddy Putluri, Arun Sreekumar, Chandrashekar R. Ambati, David H. Hawke, Jeffrey R. Marks, Preethi H. Gunaratne, Abigail S. Caudle , Aysegul A. Sahin , Gabriel N. Hortobagyi , Funda Meric-Bernstam , Lieping Chen, Dihua Yu , Mien-Chie Hung, Michael A. Curran , Leng Han, Chunru Lin and Liuqing Yang

Read more in Nature Immunology

The Polycomb Repressor Complex 1 Drives Double-Negative Prostate Cancer Metastasis by Coordinating Stemness and Immune Suppression

The mechanisms that enable immune evasion at metastatic sites are poorly understood. We show that the Polycomb Repressor Complex 1 (PRC1) drives colonization of the bones and visceral organs in double-negative prostate cancer (DNPC). In vivo genetic screening identifies CCL2 as the top prometastatic gene induced by PRC1. CCL2 governs self-renewal and induces the recruitment of M2-like tumor- associated macrophages and regulatory T cells, thus coordinating metastasis initiation with immune suppression and neoangiogenesis. A catalytic inhibitor of PRC1 cooperates with immune checkpoint therapy to reverse these processes and suppress metastasis in genetically engineered mouse transplantation models of DNPC. These results reveal that PRC1 coordinates stemness with immune evasion and neoangiogenesis and point to the potential clinical utility of targeting PRC1 in DNPC.

Wenjing Su, Hyun Ho Han, Yan Wang, Boyu Zhang, Bing Zhou, Yuanming Cheng, Alekya Rumandla, Sreeharsha Gurrapu, Goutam Chakraborty, Jie Su, Guangli Yang, Xin Liang, Guocan Wang, Neal Rosen, Howard I. Scher, Ouathek Ouerfelli and Filippo G. Giancotti

Read more in Cancer Cell

Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes

Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopoly-spora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.

Erick Riquelme, Yu Zhang, Liangliang Zhang, Maria Montiel, Michelle Zoltan, Wenli Dong, Pompeyo Quesada, Ismet Sahin, Vidhi Chandra, Anthony San Lucas, Paul Scheet, Hanwen Xu, Samir M. Hanash, Lei Feng, Jared K.Burks, Kim-Anh Do, Christine B. Peterson, Deborah Nejman, Ching-Wei D. Tzeng, Michael P. Kim, Cynthia L. Sears, Nadim Ajami, Joseph Petrosino, Laura D. Wood, Anirban Maitra, Ravid Straussman, Matthew Katz, James Robert White, Robert Jenq, Jennifer Wargo and Florencia McAllister

Read more in Cell

Induction Chemotherapy Response as a Guide for Treatment Optimization in Sinonasal Undifferentiated Carcinoma

PURPOSE: Multimodal therapy is a well-established approach for the treatment of sinonasal undifferentiated carcinoma (SNUC); however, the optimal sequence of the various treatments modalities is yet to be determined. This study aimed to assess the role of induction chemotherapy (IC) in guiding definitive therapy in patients with SNUC.

METHODS: Ninety-five previously untreated patients diagnosed with SNUC and treated between 2001 and 2018 at The University of Texas MD Anderson Cancer Center were included in the analysis. Patients were treated with curative intent and received IC before definitive locoregional therapy. The primary end point was diseasespecific survival (DSS). Secondary end points included overall and disease-free survival, disease recurrence, and organ preservation.

RESULTS: A total of 95 treatment-naïve patients were included in the analysis. For the entire cohort, the 5-years DSS probability was 59% (95% CI, 53% to 66%). In patients who had partial or complete response to IC, the 5-year DSS probabilities were 81% (95% CI, 69% to 88%) after treatment with definitive concurrent chemoradiotherapy (CRT) after IC and 54% (95% CI, 44% to 61%) after definitive surgery and postoperative radiotherapy or CRT after IC (log-rank P = .001). In patients who did not experience at least a partial response to IC, the 5-year DSS probabilities were 0% (95% CI, 0% to 4%) in patients who were treated with concurrent CRT after IC and 39% (95% CI, 30% to 46%) in patients who were treated with surgery plus radiotherapy or CRT (adjusted hazard ratio of 5.68 [95% CI, 2.89 to 9.36]).

CONCLUSION: In patients who achieve a favorable response to IC, definitive CRT results in improved survival compared with those who undergo definitive surgery. In patients who do not achieve a favorable response to IC, surgery when feasible seems to provide a better chance of disease control and improved survival.

Moran Amit, M.D., Ph.D.; Ahmed S. Abdelmeguid, M.D.; Teemaranawich Watcherporn, M.D.; Hideaki Takahashi, M.D., Ph.D.; Samantha Tam, M.D.; Diana Bell, M.D.; Renata Ferrarotto, M.D.; Bonnie Glisson, M.D.; Michael E. Kupferman, M.D.; Dianna B. Roberts, Ph.D.; Shirley Y. Su; Shaan M. Raza, M.D.; Franco DeMonte, M.D. and Ehab Y. Hanna, M.D.

Read more in Journal of Clinical Oncology

Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases

There is a critical need to improve our understanding of the pathogenesis of melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor sequencing, and IHC. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival.

Comparison with patient-matched extracranial metastases identified significant immunosuppression and enrichment of oxidative phosphorylation (OXPHOS) in MBMs. Gene-expression analysis of intracranial and subcutaneous xenografts, and a spontaneous MBM model, confirmed increased OXPHOS gene expression in MBMs, which was also detected by direct metabolite profiling and [U^-13C]-glucose tracing in vivo. IACS-010759, an OXPHOS inhibitor currently in early-phase clinical trials, improved survival of mice bearing MAPK inhibitor–resistant intracranial melanoma xenografts and inhibited MBM formation in the spontaneous MBM model. The results provide new insights into the pathogenesis and therapeutic resistance of MBMs.

SIGNIFICANCE: Improving our understanding of the pathogenesis of MBMs will facilitate the rational development and prioritization of new therapeutic strategies. This study reports the most comprehensive molecular profiling of patient-matched MBMs and extracranial metastases to date. The data provide new insights into MBM biology and therapeutic resistance.

Grant M. Fischer, Ali Jalali, David A. Kircher, Won-Chul Lee, Jennifer L. McQuade, Lauren E. Haydu, Aron Y. Joon, Alexandre Reuben, Mariana P. de Macedo, Fernando C. L. Carapeto, Chendong Yang, Anuj Srivastava, Chandrashekar R. Ambati, Arun Sreekumar, Courtney W. Hudgens, Barbara Knighton, Wanleng Deng, Sherise D. Ferguson, Hussein A. Tawbi, Isabella C. Glitza, Jeffrey E. Gershenwald, Y. N. Vashisht Gopal, Patrick Hwu, Jason T. Huse, Jennifer A. Wargo, P. Andrew Futreal, Nagireddy Putluri, Alexander J. Lazar, Ralph J. DeBerardinis, Joseph R. Marszalek, Jianjun Zhang, Sheri L. Holmen, Michael T. Tetzlaff and  Michael A. Davies

Read more in Cancer Discovery

Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality

The mitochondrial caseinolytic protease P (ClpP) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory chain protein substrates and disrupts mitochondrial structure and function, while it does not affect non-malignant cells. We identified imipridones as potent activators of ClpP. Through biochemical studies and crystallography, we show that imipridones bind ClpP non-covalently and induce proteolysis by diverse structural changes. Imipridones are presently in clinical trials. Our findings suggest a general concept of inducing cancer cell lethality through activation of mitochondrial proteolysis.

Jo Ishizawa, Sarah F. Zarabi, R.Eric Davis, Ondrej Halgas, Takenobu Nii, Yulia Jitkova, Ran Zhao, Jonathan St-Germain, Lauren E. Heese, Grace Egan, Vivian R. Ruvolo, Samir H.Barghout, Yuki Nishida, Rose Hurren, Wencai Ma, Marcela Gronda, Todd Link, Keith Wong, Mark Mabanglo, Kensuke Kojima, Gautam Borthakur, Neil MacLean, Man Chun John Ma, Andrew B. Leber, Mark D. Minden, Walid Houry, Hagop Kantarjian, Martin Stogniew, Brian Raught, Emil F. Pai, Aaron D. Schimmer and  Michael Andreeff

Read more in Cancer Cell

Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial

Precision medicine focuses on DNA abnormalities, but not all tumors have tractable genomic alterations. The WINTHER trial (NCT01856296) navigated patients to therapy on the basis of fresh biopsy-derived DNA sequencing (arm A; 236 gene panel) or RNA expression (arm B; comparing tumor to normal). The clinical management committee (investigators from five countries) recommended therapies, prioritizing genomic matches; physicians determined the therapy given. Matching scores were calculated post-hoc for each patient, according to drugs received: for DNA, the number of alterations matched divided by the total alteration number; for RNA, expression-matched drug ranks. Overall, 303 patients consented; 107 (35%; 69 in arm A and 38 in arm B) were evaluable for therapy. The median number of previous therapies was three. The most common diagnoses were colon, head and neck, and lung cancers. Among the 107 patients, the rate of stable disease ≥6 months and partial or complete response was 26.2% (arm A: 23.2%; arm B: 31.6% (P=0.37)). The patient proportion with WINTHER versus previous therapy progression- free,survival ratio of >1.5 was 22.4%, which did not meet the pre-specified primary end point. Fewer previous therapies, better performance status and higher matching score correlated with longer progression-free survival (all P<0.05, multivariate). Our study shows that genomic and transcriptomic profiling are both useful for improving therapy recommendations and patient outcome, and expands personalized cancer treatment.

Jordi Rodon, Jean-Charles Soria, Raanan Berger, Wilson H. Miller, Eitan Rubin, Aleksandra Kugel, Apostolia Tsimberidou, Pierre Saintigny, Aliza Ackerstein, Irene Braña, Yohann Loriot, Mohammad Afshar,Vincent Miller, Fanny Wunder, Catherine Bresson, Jean-François Martini, Jacques Raynaud, John Mendelsohn, Gerald Batist, Amir Onn, Josep Tabernero, Richard Schilsky, Vladimir Lazar, J. Jack Lee and Razelle Kurzrock

Read more in Nature Medicine

SETD3 is an actin histidine methyltransferase that prevents primary dystocia

For more than 50 years, the methylation of mammalian actin at histidine 73 has been known to occur. Despite the pervasiveness of His73 methylation, which we find is conserved in several model animals and plants, its function remains unclear and the enzyme that generates this modification is unknown. Here we identify SET domain protein 3 (SETD3) as the physiological actin His73 methyltransferase. Structural studies reveal that an extensive network of interactions clamps the actin peptide onto the surface of SETD3 to orient His73 correctly within the catalytic pocket and to facilitate methyl transfer. His73 methylation reduces the nucleotide-exchange rate on actin monomers and modestly accelerates the assembly of actin filaments. Mice that lack SETD3 show complete loss of actin His73 methylation in several tissues, and quantitative proteomics analysis shows that actin His73 methylation is the only detectable physiological substrate of SETD3. SETD3-deficient female mice have severely decreased litter sizes owing to primary maternal dystocia that is refractory to ecbolic induction agents. Furthermore, depletion of SETD3 impairs signal-induced contraction in primary human uterine smooth muscle cells. Together, our results identify a mammalian histidine methyltransferase and uncover a pivotal role for SETD3 and actin His73 methylation in the regulation of smooth muscle contractility. Our data also support the broader hypothesis that protein histidine methylation acts as a common regulatory mechanism.

Alex W. Wilkinson, Jonathan Diep, Shaobo Dai, Shuo Liu, Yaw Shin Ooi, Dan Song, Tie-Mei Li, John R. Horton, Xing Zhang, Chao Liu, Darshan V. Trivedi, Katherine M. Ruppel, José G. Vilches-Moure, Kerriann M. Casey, Justin Mak, Tina Cowan, Joshua E. Elias, Claude M. Nagamine, James A. Spudich, Xiaodong Cheng, Jan E. Carette and Or Gozani

Read more in Nature

METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis

Increased protein synthesis plays an etiologic role in diverse cancers. Here, we demonstrate that METTL13 (methyltransferase-like 13) dimethylationof eEF1A (eukaryotic elongation factor 1A) lysine55 (eEF1AK55me2) is utilized by Ras-driven cancers to increase translational output and promotetumorigenesis in vivo. METTL13-catalyzed eEF1A methylation increases eEF1A's intrinsic GTPase activity in vitro and protein production in cells. METTL13 and eEF1AK55me2 levels are upregulated in cancer and negatively correlate with pancreatic and lung cancer patient survival. METTL13 deletion and eEF1AK55me2 loss dramatically reduce Ras-driven neoplastic growth in mouse models and in patient-derived xenografts(PDXs) from primary pancreatic and lung tumors. Finally, METTL13 depletion renders PDX tumors hypersensitive to drugs that target growth-signaling pathways. Together, our work uncovers a mechanism by which lethal cancers become dependent on the METTL13-eEF1AK55me2 axis to meet their elevated protein synthesis requirement and suggests that METTL13 inhibition may constitute a targetable vulnerability of tumors driven by aberrant Ras signaling.

Shuo Liu, Simone Hausmann, Scott Moore Carlson, Mary Esmeralda Fuentes, Joel William Francis, Renjitha Pillai, Shane Michael Lofgren, Laura Hulea, Kristofferson Tandoc, Jiuwei Lu, Ami Li, Nicholas Dang Nguyen, Marcello Caporicci, Michael Paul Kim, Anirban Maitra, Huamin Wang, Ignacio Ivan Wistuba, John Anthony Porco Jr., Michael Cory Bassik, Joshua Eric Elias, Jikui Song, Ivan Topisirovic, Capucine Van Rechem, Pawel Karol Mazur and Or Gozani

Read more in Cell

Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis

We report the first case series of immune checkpoint inhibitors (ICI)-associated colitis successfully treated with fecal microbiota transplantation, with reconstitution of the gut microbiome and a relative increase in the proportion of regulatory T-cells within the colonic mucosa. These preliminary data provide evidence that modulation of the gut microbiome may abrogate ICI-associated colitis.

Yinghong Wang, Diana H. Wiesnoski, Beth A. Helmink, Vancheswaran Gopalakrishnan, Kati Choi, Hebert L. DuPont, Zhi-Dong Jiang, Hamzah Abu-Sbeih, Christopher A. Sanchez, Chia-Chi Chang, Edwin R. Parra, Alejandro Francisco-Cruz, Gottumukkala S. Raju, John R. Stroehlein, Matthew T. Campbell, Jianjun Gao, Sumit K. Subudhi, Dipen M. Maru, Jorge M. Blando, Alexander J. Lazar, James P. Allison, Padmanee Sharma, Michael T. Tetzlaff, Jennifer A. Wargo and Robert R. Jenq

Read more in Nature Medicine

CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade

Although treatment with immune checkpoint inhibitors provides promising benefit for patients with cancer, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the upregulation of CD38, which is induced by all-trans retinoic acid and IFNβ in the tumor microenvironment. In vitro and in vivo studies demonstrate that CD38 inhibits CD8⁺ T-cell function via adenosine receptor signaling and that CD38 or adenosine receptor blockade are effective strategies to overcome the resistance. Large data sets of human tumors reveal expression of CD38 in a subset of tumors with high levels of basal or treatment-induced T-cell infiltration, where immune checkpoint therapies are thought to be most effective. These findings provide a novel mechanism of acquired resistance to immune checkpoint therapy and an opportunity to expand their efficacy in cancer treatment.

SIGNIFICANCE: CD38 is a major mechanism of acquired resistance to PD-1/PD-L1 blockade, causing CD8⁺ T-cell suppression. Coinhibition of CD38 and PD-L1 improves antitumor immune response. Biomarker assessment in patient cohorts suggests that a combination strategy is applicable to a large percentage of patients in whom PD-1/PD-L1 blockade is currently indicated.

Limo Chen, Lixia Diao, Yongbin Yang, Xiaohui Yi, B. Leticia Rodriguez, Yanli Li, Pamela A. Villalobos, Tina Cascone, Xi Liu, Lin Tan, Philip L. Lorenzi, Anfei Huang, Qiang Zhao, Di Peng, Jared J. Fradette, David H. Peng, Christin Ungewiss, Jonathon Roybal, Pan Tong, Junna Oba, Ferdinandos Skoulidis, Weiyi Peng, Brett W. Carter, Carl M. Gay, Youhong Fan, Caleb A. Class, Jingfen Zhu, Jaime Rodriguez-Canales, Masanori Kawakami, Lauren Averett Byers, Scott E. Woodman, Vassiliki A. Papadimitrakopoulou, Ethan Dmitrovsky, Jing Wang, Stephen E. Ullrich, Ignacio I. Wistuba, John V. Heymach, F. Xiao-Feng Qin and Don L. Gibbons

Read more in Cancer Discovery

Minimally Invasive versus Abdominal Radical Hysterectomy for Cervical Cancer

BACKGROUND: There are limited data from retrospective studies regarding whether survival outcomes after laparoscopic or robot-assisted radical hysterectomy (minimally invasive surgery) are equivalent to those after open abdominal radical hysterectomy (open surgery) among women with early-stage cervical cancer.

RESULTS: A total of 319 patients were assigned to minimally invasive surgery and 312 to open surgery. Of the patients who were assigned to and underwent minimally invasive surgery, 84.4% underwent laparoscopy and 15.6% robot-assisted surgery. Overall, the mean age of the patients was 46.0 years. Most patients (91.9%) had stage IB1 disease. The two groups were similar with respect to histologic subtypes, the rate of lymphovascular invasion, rates of parametrial and lymph-node involvement, tumor size, tumor grade, and the rate of use of adjuvant therapy. The rate of disease-free survival at 4.5 years was 86.0% with minimally invasive surgery and 96.5% with open surgery, a difference of -10.6 percentage points (95% confidence interval [CI], -16.4 to -4.7). Minimally invasive surgery was associated with a lower rate of disease-free survival than open surgery (3-year rate, 91.2% vs. 97.1%; hazard ratio for disease recurrence or death from cervical cancer, 3.74; 95% CI, 1.63 to 8.58), a difference that remained after adjustment for age, body-mass index, stage of disease, lymphovascular invasion, and lymph-node involvement; minimally invasive surgery was also associated with a lower rate of overall survival (3-year rate, 93.8% vs. 99.0%; hazard ratio for death from any cause, 6.00; 95% CI, 1.77 to 20.30).

CONCLUSION: In this trial, minimally invasive radical hysterectomy was associated with lower rates of disease-free survival and overall survival than open abdominal radical hysterectomy among women with early-stage cervical cancer.

Pedro T. Ramirez, Michael Frumovitz, Rene Pareja, Aldo Lopez, Marcelo Vieira, Reitan Ribeiro, Alessandro Buda, Xiaojian Yan, Yao Shuzhong, Naven Chetty, David Isla, Mariano Tamura, Tao Zhu, Kristy P. Robledo, Val Gebski, Rebecca Asher, Vanessa Behan, James L. Nicklin, Robert L. Coleman and Andreas Obermair

Read more in The New England Journal of Medicine