Featured
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Research Briefing |
Stress response in tumor-infiltrating T cells is linked to immunotherapy resistance
A newly composed single-cell transcriptomic atlas of tumor-infiltrating T cells across 16 cancer types revealed previously undescribed T cell states and heterogeneity. A unique T cell stress response state, TSTR, was linked to immunotherapy resistance. Our high-resolution T cell reference maps, web portal, and annotation tool can assist efforts to develop T cell therapies.
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Resource |
Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance
A single-cell analysis of tumor-infiltrating T cells from 16 cancer types identifies new T cell subsets and a stress response cell state enriched in tumors resistant to immunotherapy.
- Yanshuo Chu
- , Enyu Dai
- & Linghua Wang
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News & Views |
Advancing combination therapy for recurrent glioblastoma
Adding an oncolytic virus to classic immune checkpoint inhibition elicits treatment responses and survival benefit for select immunologically ‘cold’ recurrent glioblastomas, although creative treatment strategies are still needed for patients with highly anti-inflammatory tumors.
- Adela Wu
- & Michael Lim
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Article
| Open Access
Evolution of synchronous female bilateral breast cancers and response to treatment
Clinical, genomic and transcriptomic analyses of paired samples of synchronous bilateral female breast cancer identify associations between tumor concordance and immune infiltrates levels and response to neoadjuvant treatment.
- Anne-Sophie Hamy
- , Judith Abécassis
- & Fabien Reyal
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Article
| Open Access
Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma
Analysis of tumor biopsies from the pivotal phase 1/2 ZUMA-1 trial identifies pre-treatment T cell–related characteristics that are associated with clinical response and neurologic toxicity after anti-CD19 CAR T cell therapy in patients with large B cell lymphoma.
- Nathalie Scholler
- , Regis Perbost
- & Jérôme Galon
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Article |
Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma
Single-cell transcriptional profiling of primary human synovial sarcoma tumors suggests that combinatorial treatment with HDAC and CDK4/CDK6 inhibitors could enhance tumor immunogenicity.
- Livnat Jerby-Arnon
- , Cyril Neftel
- & Aviv Regev
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Article |
Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state
Tumor-secreted midkine modulates immune tolerance in the melanoma tumor microenvironment and determines resistance to immune checkpoint blockade.
- Daniela Cerezo-Wallis
- , Marta Contreras-Alcalde
- & María S. Soengas
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Letter |
A single-cell landscape of high-grade serous ovarian cancer
Single-cell transcriptomics analysis of malignant ascites samples from patients with high-grade serous ovarian cancer reveals inter- and intra-patient heterogeneity in malignant cells, cancer-associated fibroblasts and macrophages.
- Benjamin Izar
- , Itay Tirosh
- & Aviv Regev
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Letter |
High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade
In a retrospective analysis of data from three clinical trials, increased baseline peripheral and tumor IL-8 levels were associated with worse clinical outcomes in patients with metastatic urothelial carcinoma and metastatic renal cell carcinoma treated with anti-PD-L1 therapy.
- Kobe C. Yuen
- , Li-Fen Liu
- & Sanjeev Mariathasan
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Article |
Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy
Blockade of sialic acid-binding protein Siglec-15 expressed in cancer and tumor-infiltrating myeloid cells reverses immunesupression and represents a novel target for cancer immunotherapy independent from the PD-1/PD-L1 axis.
- Jun Wang
- , Jingwei Sun
- & Lieping Chen
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Article |
Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma
Neoadjuvant pembrolizumab promotes a survival benefit with intratumoral and systemic immune responses in patients with recurrent glioblastoma.
- Timothy F. Cloughesy
- , Aaron Y. Mochizuki
- & Robert M. Prins
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Letter |
Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma
Neoadjuvant combination treatment with nivolumab and ipilimumab in patients with high-risk melanoma results in higher response rates than nivolumab monotherapy and warrants future optimization of dosing regimens to preserve efficacy while limiting toxicity.
- Rodabe N. Amaria
- , Sangeetha M. Reddy
- & Jennifer A. Wargo
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Letter |
Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells
Large tumors induce anemia and expansion of CD45+ immature erythroid cells, which represent a major immunosuppressive population in the spleen, contributing to systemic suppression of T cell immunity in late-stage cancer.
- Lintao Zhao
- , Ran He
- & Bo Zhu
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Letter |
Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses
Retroelements located in antisense orientation within interferon-regulated genes are reactivated in a subset of cancer cells and initiate a STING- and MAVS-dependent feed-forward inflammatory loop, driving antitumor immunity and exhaustion.
- Israel Cañadas
- , Rohit Thummalapalli
- & David Allen Barbie
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Article |
Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate
An oncometabolite produced by tumor cells acts as a paracrine immunosuppressant dampening antitumor T cell responses in glioma.
- Lukas Bunse
- , Stefan Pusch
- & Michael Platten
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Resource |
Phenotype molding of stromal cells in the lung tumor microenvironment
A comprehensive single-cell analysis of the lung cancer microenvironment reveals marked heterogeneity of transcriptional networks that defines novel clinically relevant stromal cell populations.
- Diether Lambrechts
- , Els Wauters
- & Bernard Thienpont
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Letter |
Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis
Extensive, high-dimensional characterization of T cells in breast cancer reveals activated TRM population and a gene signature associated with improved prognosis.
- Peter Savas
- , Balaji Virassamy
- & Sherene Loi
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Article |
A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments
Cross-talk between innate immune cells helps to enhance the antitumor T cell response during checkpoint blockade therapy.
- Kevin C. Barry
- , Joy Hsu
- & Matthew F. Krummel
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Article |
A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade
Tumor-infiltrating CD8+ T cells with high expression of PD-1 in non-small-cell lung cancer are distinct from exhausted T cells in chronic virus infection, have high tumor reactivity and associate with response to PD-1-targeted immunotherapy.
- Daniela S. Thommen
- , Viktor H. Koelzer
- & Alfred Zippelius
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Review Article |
Understanding the tumor immune microenvironment (TIME) for effective therapy
The tumor immune microenvironment influences tumor progression and response to immunotherapy; its further characterization will improve therapeutic outcome.
- Mikhail Binnewies
- , Edward W. Roberts
- & Matthew F. Krummel
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Article |
Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling
Paracrine signaling networks in the breast cancer microenvironment uncover determinants of hormone receptor status and offer opportunities for therapeutic intervention.
- Pernilla Roswall
- , Matteo Bocci
- & Kristian Pietras
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Article |
Diverse genetic-driven immune landscapes dictate tumor progression through distinct mechanisms
Pier Paolo Pandolfi and colleagues report that the genetic background of tumors in mice recruits specific immune-cell subsets, suggesting that precision medicine should account for both the tumor drivers and the distinct immune-cell microenvironments that they elicit.
- Marco Bezzi
- , Nina Seitzer
- & Pier Paolo Pandolfi
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Article |
Targeting glioma stem cells through combined BMI1 and EZH2 inhibition
Microenvironmental pressures in glioblastoma select for glioma stem cells (GSCs) subpopulations that are maintained through preferential activation of BMI1 and EZH2 in different niches. Given the high degree of intratumor heterogeneity, combined pharmacological inhibition of Polycomb repressive complexes targets proneural and mesenchynmal GSCs and expands lifespan in mice, warranting the therapeutic evaluation of this approach in patients with glioblastoma.
- Xun Jin
- , Leo J Y Kim
- & Jeremy N Rich
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Article |
KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis
Factors secreted by metastatic a primary tumors induce an early phenotypic switch in perivascular cells at distant pre-metastatic niches. By using sophisticated lineage-tracing mouse models, the authors demonstrate that enhanced KLF4 expression in these cells increases their ability to proliferate and migrate away from the vasculature, and augments fibronectin deposition, which contributes to metastatic growth. These findings increase the mechanistic understanding of the metastatic process and uncover a role for perivascular plasticity that could be targeted to prevent metastasis.
- Meera Murgai
- , Wei Ju
- & Rosandra N Kaplan
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Technical Report |
ISDoT: in situ decellularization of tissues for high-resolution imaging and proteomic analysis of native extracellular matrix
By surgically directing the vascular delivery of decellularization reagents, the in situ decellularization of desired organs or tissues in mice can be achieved, enabling detailed imaging and characterization of the intact extracellular matrix, including in the cancer metastatic niche.
- Alejandro E Mayorca-Guiliani
- , Chris D Madsen
- & Janine T Erler
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Article |
Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance
Activation of dectin-1-dependent signaling in macrophages through ligation by galectin 9 promotes an immunosuppressive, protumorigenic microenvironment in pancreatic adenocarcinoma (PDA). Blocking dectin 1 ligation restores anti-tumor immunity and delays tumor growth, thus offering a novel strategy for improving the effectiveness of immunotherapy in patients with PDA.
- Donnele Daley
- , Vishnu R Mani
- & George Miller
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News & Views |
Improving treatment of liver metastases by targeting nonangiogenic mechanisms
A recent study confirms an association between vessel co-option and resistance to bevacizumab, an anti-vascular endothelial growth factor-A (VEGFA) antibody, in patients with liver metastases. The authors suggest a combined therapeutic strategy that reduces co-option in mice.
- Kyrre E Emblem
- & Rakesh K Jain
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Article |
Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy
DeNardo and colleagues report that inhibiting focal adhesion kinase in pancreatic ductal adenocarcinoma (PDAC) in mice reduces fibrosis and improves the efficacy of tumor immunotherapy. These findings suggest an approach to overcome the immunosuppressive tumor microenvironment of PDAC.
- Hong Jiang
- , Samarth Hegde
- & David G DeNardo
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Technical Report |
A humanized bone marrow ossicle xenotransplantation model enables improved engraftment of healthy and leukemic human hematopoietic cells
Mice bearing ossicles containing human bone marrow stromal cells enable improved leukemia engraftment and detection of high frequencies of human leukemia-initiating cells.
- Andreas Reinisch
- , Daniel Thomas
- & Ravindra Majeti
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News & Views |
Regulation of pancreatic cancer aggressiveness by stromal stiffening
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive stromal component that hinders treatment. A new study shows how the genetic identity of pancreatic tumors might influence the physical properties of the associated stroma to promote tumor progression.
- Nicola Rath
- & Michael F Olson
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Article |
Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression
Impaired TGF-β signaling due to SMAD4 mutation in PDAC tumors initiates a STAT3-dependent signaling cascade that leads to increased stromal stiffening and disease progression.
- Hanane Laklai
- , Yekaterina A Miroshnikova
- & Valerie M Weaver
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Perspective |
Toward understanding and exploiting tumor heterogeneity
In this Perspective, attendees of the Herrenhausen Tumour Heterogeneity meeting discuss the challenges in understanding tumour heterogeneity and propose ways forward for overcoming these hurdles.
- Ash A Alizadeh
- , Victoria Aranda
- & Jessica Zucman-Rossi
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News & Views |
ECM stiffness paves the way for tumor cells
In the mammary gland, the stiffness of extracellular matrix (ECM) collagen is thought to influence tumor progression and clinical outcome. A new mechanism orchestrated by a microRNA circuit is shown to mediate the physical effects of the microenvironment on tumor cell progression. The findings may explain how increased breast matrix stiffness is associated with poor survival and could help identify women with aggressive breast cancer (pages 360–367).
- Victoria Seewaldt
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Article |
Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression
Mouw et al. delineate a molecular pathway by which matrix stiffness promotes tumor malignancy. Upon matrix stiffening, integrin signaling is engaged, triggering a signaling cascade that regulates the protumorigenic microRNA miR-18a. This leads to downregulation of PTEN and activation of oncogenic signaling. The pathway provides a link between mechanotransduction, miR regulation and oncogene activation that integrates biophysical changes into tumor progression and can also be altered in human tumors.
- Janna K Mouw
- , Yoshihiro Yui
- & Valerie M Weaver
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Editorial |
Keeping pace with cancer
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Review Article |
Microenvironmental regulation of tumor progression and metastasis
Cancer cells can alter and build a permissive microenvironment that supports the malignant behavior of a growing primary tumor and developing metastases. But the role of the players in the stroma is rather complex, and their functions are intertwined, requiring a strategy to normalize the microenvironment to halt cancer progression. Re-education of stromal cells that interact with tumor cells may be a promising therapeutic avenue to exploit a genetically stable part of the tumor.
- Daniela F Quail
- & Johanna A Joyce
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News & Views |
Therapeutically reeducating macrophages to treat GBM
Glioblastoma multiforme (GBM) is the most common type of aggressive malignant brain cancer. The current lack of successful therapeutics means that this disease has a dismal prognosis. However, a new study in mice offers hope for patients with GBM by demonstrating the efficacy of a novel drug that targets GBM-associated macrophages (pages 1264–1272).
- Christopher Garris
- & Mikael J Pittet
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Article |
Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth
Gemcitabine and 5-fluorouracil are two commonly used chemotherapeutic agents for the treatment of cancer. François Ghiringhelli and colleagues now report that the antitumor efficacy of these agents is mitigated by myeloid derived suppressor cells (MDSCs). The authors show that these drugs can activate the NLRP3 inflammasome, leading to increased secretion of IL-1β by MDSCs and IL-17 production by CD4+ T cells, which can promote tumor growth.
- Mélanie Bruchard
- , Grégoire Mignot
- & François Ghiringhelli
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News & Views |
The tumor microenvironment controls drug sensitivity
A better understanding of mechanisms involved in regulation of drug sensitivity is crucial for improved cancer treatment. New studies show that cells of the tumor microenvironment modulate the response of cancer cells to chemotherapy and targeted therapies through production of secreted factors (pages 1359–1368).
- Arne Östman
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Article |
Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B
Responses to anticancer therapy are hampered by several factors, and Peter S. Nelson and colleagues here identify a protective effect of the tumor microenvironment. After cytotoxic chemotherapy, inflammatory NF-κB signaling activates the secretion of WNT16B, which acts on epithelial cells, promoting their survival and fostering tumor growth in vivo. This pathway is also active in human tumors treated with chemotherapy and illustrates the potential caveats of cyclical therapy and the need to overcome environmental protection to successfully eliminate tumors.
- Yu Sun
- , Judith Campisi
- & Peter S Nelson
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Review Article |
Tumor angiogenesis: molecular pathways and therapeutic targets
- Sara M Weis
- & David A Cheresh
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Letter |
Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth
Ovarian tumors preferentially metastasize to the omentum, a peritoneal fat layer. This report proposes that the reasons for this predilection stem from the growth advantage conferred by adipocytes on ovarian cancer cells. Adipocytes seem to promote homing of cancer cells through adipokine secretion, and direct contact of the two cell types promotes metabolic changes that result in lipid transfer from adipocytes to tumor cells. Environmental-driven metabolic adaptations could be exploited to target omental metastasis.
- Kristin M Nieman
- , Hilary A Kenny
- & Ernst Lengyel
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News & Views |
Resistance, epigenetics and the cancer ecosystem
Therapeutic resistance is a key roadblock to effective cancer treatment and can occur through various mechanisms. A recent study characterized a previously unknown, reversible mechanism of drug resistance mediated by an altered chromatin state, suggesting that cancer cell populations can use a dynamic strategy to ensure their survival when challenged by therapeutic intervention.
- Stephen B Baylin
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Review Article |
Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression
- Mina J Bissell
- & William C Hines
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Article |
STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors
Physiological Stat3 signaling is temporally restricted. In cancer, Stat3 activity is often persistently elevated and fosters progression through its effects on tumor cells and their microenvironment. This report identifies the reciprocal positive regulation of S1PR1 and Stat3 in tumors as a mechanism by which tumor cells and their environment crosstalk to maintain Stat3 activity. This persistent loop is required for tumor progression and metastasis and could be a potential therapeutic target to block oncogenic Stat3 signaling.
- Heehyoung Lee
- , Jiehui Deng
- & Hua Yu
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Article |
Allosteric inhibition of lysyl oxidase–like-2 impedes the development of a pathologic microenvironment
Pathologically altered stromas are a common contributing factor to cancer progression and fibrogenesis. This report uncovers the role of LOXL2 in the creation and maintenance of the pathological microenvironment of human cancers and fibrotic diseases and presents the development of a LOXL2-specific antibody that shows therapeutic activity in tumor as well as lung and liver fibrosis models.
- Vivian Barry-Hamilton
- , Rhyannon Spangler
- & Victoria Smith
Neoadjuvant adebrelimab in locally advanced resectable esophageal squamous cell carcinoma: a phase 1b trial
Let's get physical: mechanical forces drive a new field of study