Research is a cornerstone of MD Anderson’s quest to end cancer. The Excellence in Science program is the online showcase for the Wall of Science, our quarterly program for honoring outstanding primary research selected from among publications in top journals by MD Anderson’s world-renowned scientists.
2021 Quarter 4 Awardees
Dr. Ajani
First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma - The Lancet
Dr. Di Pilato
CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment — Cell
Dr. Fowler
Conserved pan-cancer microenvironment subtypes predict response to immunotherapy — Cancer Cell
Drs. Haymaker and Diab
Tilsotolimod with Ipilimumab drives tumor responses in Anti–PD-1 Refractory Melanoma — Cancer Discovery
Drs. Tsai and Tainer
EXO5-DNA structure and BLM interactions direct DNA resection critical for ATR-dependent replication restart - Molecular Cell
Drs. Ye, Tainer, and Ahmed
GRB2 enforces homology-directed repair initiation by MRE11 — Science Advances
Drs. Zhang, Lin, and Yang
A noncoding RNA modulator potentiates phenylalanine metabolism in mice — Science
June – August 2021
Jaffer A. Ajani, M.D.
The Lancet
First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial
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Nathan Fowler, M.D.
Cancer Cell
Conserved pan-cancer microenvironment subtypes predict response to immunotherapy
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Chi-Lin Tsai, Ph.D. | John Tainer, Ph.D.
Molecular Cell
EXO5-DNA structure and BLM interactions direct DNA resection critical for ATR-dependent replication restart
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Shuxing Zhang, Ph.D., Pharm.D. | Chunru Lin, M.D., Ph.D. | Liuqing Yang, Ph.D.
Science
A noncoding RNA modulator potentiates phenylalanine metabolism in mice
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Mauro Di Pilato, Ph.D.
Cell
CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment
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Cara Haymaker, Ph.D. | Adi Diab, M.D.
Cancer Discovery
Tilsotolimod with Ipilimumab drives tumor responses in Anti–PD-1 Refractory Melanoma
Read more
Zu Ye, Ph.D. | John Tainer, Ph.D. | Zamal Ahmed, Ph.D.
Science Advances
GRB2 enforces homology-directed repair initiation by MRE11
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Jaffer A. Ajani, M.D.
First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial
First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone.
Yelena Y. Janjigian, Kohei Shitara, Markus Moehler, Marcelo Garrido, Pamela Salman, Lin Shen, Lucjan Wyrwicz, Kensei Yamaguchi, Tomasz Skoczylas, Arinilda Campos Bragagnoli, Tianshu Liu, Michael Schenker, Patricio Yanez, Mustapha Tehfe, Ruben Kowalyszyn, Michalis V. Karamouzis, Ricardo Bruges, Thomas Zander, Roberto Pazo-Cid, Erika Hitre, Kynan Feeney, James M. Cleary, Valerie Poulart, Dana Cullen, Ming Lei, Hong Xiao, Kaoru Kondo, Mingshun Li, Jaffer A. Ajani
Overall survival advantage. Click to enlarge.
Jaffer A. Ajani, M.D.
Mauro Di Pilato, Ph.D.
Mauro Di Pilato, Ph.D.
CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment
Cytotoxic T lymphocyte (CTL) responses against tumors are maintained by stem-like memory cells that self-renew but also give rise to effector-like cells. The latter gradually lose their anti-tumor activity and acquire an epigenetically fixed, hypofunctional state, leading to tumor tolerance. Here, we show that the conversion of stem-like into effector-like CTLs involves a major chemotactic reprogramming that includes the upregulation of chemokine receptor CXCR6. This receptor positions effector-like CTLs in a discrete perivascular niche of the tumor stroma that is densely occupied by CCR7+ dendritic cells (DCs) expressing the CXCR6 ligand CXCL16. CCR7+ DCs also express and trans-present the survival cytokine interleukin-15 (IL-15). CXCR6 expression and IL-15 trans-presentation are critical for the survival and local expansion of effector-like CTLs in the tumor microenvironment to maximize their anti-tumor activity before progressing to irreversible dysfunction. These observations reveal a cellular and molecular checkpoint that determines the magnitude and outcome of anti-tumor immune responses.
Mauro Di Pilato, Raphael Kfuri-Rubens, Jasper N. Pruessmann, Aleksandra J. Ozga, Marius Messemaker, Bruno L. Cadilha, Ramya Sivakumar, Chiara Cianciaruso, Ross D. Warner, Francesco Marangoni, Esteban Carrizosa, Stefanie Lesch, James Billingsley, Daniel Perez-Ramos, Fidel Zavala, Esther Rheinbay, Andrew D. Luster, Michael Y. Gerner, Sebastian Kobold, Mikael J. Pittet, Thorsten R. Mempel
CXCR6+ effector-like cytotoxic T lymphocytes (CTL) are guided into
perivascular niches of the tumor stroma that is densely occupied by
CCR7+ conventional dendritic cells (cDC) expressing the CXCR6-ligand
CXCL16. By secreting and trans-presenting the pro-survival cytokine
IL-15 and its receptor IL-15ra, CCR7+ cDC avoid CTL cell death and
induce CTL expansion. Finally, these transitory proliferating CTL
control tumor before to become irreversibly dysfunctional cells. Click
to enlarge.
Nathan Fowler, M.D.
Conserved pan-cancer microenvironment subtypes predict response to immunotherapy
The clinical use of molecular targeted therapy is rapidly evolving but has primarily focused on genomic alterations. Transcriptomic analysis offers an opportunity to dissect the complexity of tumors, including the tumor microenvironment (TME), a crucial mediator of cancer progression and therapeutic outcome. TME classification by transcriptomic analysis of >10,000 cancer patients identifies four distinct TME subtypes conserved across 20 different cancers. The TME subtypes correlate with patient response to immunotherapy in multiple cancers, with patients possessing immune-favorable TME subtypes benefiting the most from immunotherapy. Thus, the TME subtypes act as a generalized immunotherapy biomarker across many cancer types due to the inclusion of malignant and microenvironment components. A visual tool integrating transcriptomic and genomic data provides a global tumor portrait, describing the tumor framework, mutational load, immune composition, anti-tumor immunity, and immunosuppressive escape mechanisms. Integrative analyses plus visualization may aid in biomarker discovery and the personalization of therapeutic regimens.
Alexander Bagaev, Nikita Kotlov, Krystle Nomie, Viktor Svekolkin, Azamat Gafurov, Olga Isaeva, Nikita Osokin, Ivan Kozlov, Felix Frenkel, Olga Gancharova, Nava Almog, Maria Tsiper, Ravshan Ataullakhanov, Nathan Fowler
For this research study, tumor transcriptome sequencing was analyzed to
holistically describe and comprehensively characterize cancer cells and
the surrounding tumor microenvironment. Transcriptomic data of over
10,000 cancer patients were analyzed, leading to the identification of
four unique microenvironment subtypes that are conserved across 20
different cancers. These four subtypes are strongly associated with
prognosis and response to immunotherapy in different cancers. Click to enlarge.
Nathan Fowler, M.D.
Cara Haymaker, Ph.D. & Adi Diab, M.D.
Cara Haymaker, Ph.D.
Adi Diab, M.D.
Tilsotolimod with Ipilimumab drives tumor responses in Anti–PD-1 Refractory Melanoma
Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti–PD-1– resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNα gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing
Significance: Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone.
Cara Haymaker, Daniel H. Johnson, Ravi Murthy, Salah Eddine Bentebibel, Marc I. Uemura, Courtney W. Hudgens, Houssein Safa, Marihella James, Robert H.I. Andtbacka, Douglas B. Johnson, Montaser Shaheen, Michael A. Davies, Shah Rahimian, Srinivas K. Chunduru, Denái R. Milton, Michael T. Tetzlaff, Willem W. Overwijk, Patrick Hwu, Nashat Gabrail, Sudhir Agrawal, Gary Doolittle, Igor Puzanov, Joseph Markowitz, Chantale Bernatchez, Adi Diab
Adi Diab, M.D., Cara Haymaker, Ph.D., Chantale Bernatchez, Ph.D.
Chi-Lin Tsai, Ph.D. & John Tainer, Ph.D.
EXO5-DNA structure and BLM interactions direct DNA resection critical for ATR-dependent replication restart
Stalled DNA replication fork restart after stress as orchestrated by ATR kinase, BLM helicase, and structure-specific nucleases enables replication, cell survival, and genome stability. Here we unveil human exonuclease V (EXO5) as an ATR-regulated DNA structure-specific nuclease and BLM partner for replication fork restart. We find that elevated EXO5 in tumors correlates with increased mutation loads and poor patient survival, suggesting that EXO5 upregulation has oncogenic potential. Structural, mechanistic, and mutational analyses of EXO5 and EXO5-DNA complexes reveal a single-stranded DNA binding channel with an adjacent ATR phosphorylation motif (T88Q89) that regulates EXO5 nuclease activity and BLM binding identified by mass spectrometric analysis. EXO5 phospho-mimetic mutant rescues the restart defect from EXO5 depletion that decreases fork progression, DNA damage repair, and cell survival. EXO5 depletion furthermore rescues survival of FANCA-deficient cells and indicates EXO5 functions epistatically with SMARCAL1 and BLM. Thus, an EXO5 axis connects ATR and BLM in directing replication fork restart.
Shashank Hambarde, Chi Lin Tsai, Raj K. Pandita, Albino Bacolla, Anirban Maitra, Vijay Charaka, Clayton R. Hunt, Rakesh Kumar, Oliver Limbo, Remy Le Meur, Walter J. Chazin, Susan E. Tsutakawa, Paul Russell, Katharina Schlacher, Tej K. Pandita, John A. Tainer
Graphical Abstract: Proposed mechanism of EXO5 involved in stalled
replication fork restart. EXO5 is phosphorylated by ATR kinase during
replication stress and recruited by BLM helicase to RPA-bound stalled
forks. 5’-ssDNA from the [4Fe-4S] cluster region threads under EXO5
crossover-helix. RPA guides EXO5 5’-3’ resection, while BLM unwinds the
reversed fork for restart, which is counterbalanced with fork protection
function in Fanconi anemia (FA) pathway. Depletion of EXO5 decreases
cell survival, yet it rescues cell survival in FA-deficient cells. Click
to enlarge.
Chi-Lin Tsai, Ph.D.
John Tainer, Ph.D.
Zu Ye, Ph.D., John Tainer, Ph.D., and Zamal Ahmed, Ph.D.
Zu Ye, Ph.D.
John Tainer, Ph.D.
Zamal Ahmed, Ph.D.
GRB2 enforces homology-directed repair initiation by MRE11
DNA double-strand break (DSB) repair is initiated by MRE11 nuclease for both homology-directed repair (HDR) and alternative end joining (Alt-EJ). Here, we found that GRB2, crucial to timely proliferative RAS/MAPK pathway activation, unexpectedly forms a biophysically validated GRB2-MRE11 (GM) complex for efficient HDR initiation. GRB2-SH2 domain targets the GM complex to phosphorylated H2AX at DSBs. GRB2 K109 ubiquitination by E3 ubiquitin ligase RBBP6 releases MRE11 promoting HDR. RBBP6 depletion results in prolonged GM complex and HDR defects. GRB2 knockout increased MRE11-XRCC1 complex and Alt-EJ. Reconstitution with separation-of-function GRB2 mutant caused HDR deficiency and synthetic lethality with PARP inhibitor. Cell and cancer genome analyses suggest biomarkers of low GRB2 for noncanonical HDR deficiency and high MRE11 and GRB2 expression for worse survival in HDR-proficient patients. These findings establish GRB2’s role in binding, targeting, and releasing MRE11 to promote efficient HDR over Alt-EJ DSB repair, with implications for genome stability and cancer biology.
Zu Ye, Shengfeng Xu, Yin Shi, Albino Bacolla, Aleem Syed, Davide Moiani, Chi Lin Tsai, Qiang Shen, Guang Peng, Paul G. Leonard, Darin E. Jones, Bin Wang, John A. Tainer, Zamal Ahmed
Zu Ye, Ph.D., Zamal Ahmed, Ph.D., John Tainer, Ph.D.
Shuxing Zhang, Ph.D., Pharm.D., Chunru Lin, M.D., Ph.D., and Liuqing Yang, Ph.D.
A noncoding RNA modulator potentiates phenylalanine metabolism in mice
The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-HULC mimics reduced excessive Phe in Pair -/- and Pah R408W/R408W mice and improved the Phe tolerance of these mice.
Yajuan Li, Zhi Tan, Yaohua Zhang, Zhao Zhang, Qingsong Hu, Ke Liang, Yao Jun, Youqiong Ye, Yi Chuan Li, Chunlai Li, Lan Liao, Jianming Xu, Zhen Xing, Yinghong Pan, Sujash S. Chatterjee, Tina K. Nguyen, Heidi Hsiao, Sergey D. Egranov, Nagireddy Putluri, Cristian Coarfa, David H. Hawke, Preethi H. Gunaratne, Kuang Lei Tsai, Leng Han, Mien Chie Hung, George A. Calin, Fares Namour, Jean Louis Guéant, Ania C. Muntau, Nenad Blau, V. Reid Sutton, Manuel Schiff, François Feillet, Shuxing Zhang, Chunru Lin, Liuqing Yang
Top Row (L-R): Liuqing Yang, Yaohua Zhang, Chengcao Sun, Zilong Zhao ;
Middle Row (L-R): Lisa Huang, Tina Nguyen, Pengju Gong, Chunru Lin
Shuxing Zhang, Ph.D., Pharm.D.
Chunru Lin, M.D., Ph.D.
Liuqing Yang, Ph.D.