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Susan kaech

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https://www.readbyqxmd.com/read/29899823/metformin-exerts-antitumor-activity-via-induction-of-multiple-death-pathways-in-tumor-cells-and-activation-of-a-protective-immune-response
#1
Felipe V Pereira, Amanda Campelo L Melo, Jun Siong Low, Íris Arantes de Castro, Tárcio T Braga, Danilo C Almeida, Ana Gabriela U Batista de Lima, Meire I Hiyane, Matheus Correa-Costa, Vinicius Andrade-Oliveira, Clarice S T Origassa, Rosana M Pereira, Susan M Kaech, Elaine G Rodrigues, Niels Olsen S Câmara
The antitumor effect of metformin has been demonstrated in several types of cancer; however, the mechanisms involved are incompletely understood. In this study, we showed that metformin acts directly on melanoma cells as well as on the tumor microenvironment, particularly in the context of the immune response. In vitro , metformin induces a complex interplay between apoptosis and autophagy in melanoma cells. The anti-metastatic activity of metformin in vivo was assessed in several mouse models challenged with B16F10 cells...
May 25, 2018: Oncotarget
https://www.readbyqxmd.com/read/29625895/klrg1-effector-cd8-t-cells-lose-klrg1-differentiate-into-all-memory-t-cell-lineages-and-convey-enhanced-protective-immunity
#2
Dietmar Herndler-Brandstetter, Harumichi Ishigame, Ryo Shinnakasu, Valerie Plajer, Carmen Stecher, Jun Zhao, Melanie Lietzenmayer, Lina Kroehling, Akiko Takumi, Kohei Kometani, Takeshi Inoue, Yuval Kluger, Susan M Kaech, Tomohiro Kurosaki, Takaharu Okada, Richard A Flavell
Protective immunity against pathogens depends on the efficient generation of functionally diverse effector and memory T lymphocytes. However, whether plasticity during effector-to-memory CD8+ T cell differentiation affects memory lineage specification and functional versatility remains unclear. Using genetic fate mapping analysis of highly cytotoxic KLRG1+ effector CD8+ T cells, we demonstrated that KLRG1+ cells receiving intermediate amounts of activating and inflammatory signals downregulated KLRG1 during the contraction phase in a Bach2-dependent manner and differentiated into all memory T cell linages, including CX3 CR1int peripheral memory cells and tissue-resident memory cells...
April 17, 2018: Immunity
https://www.readbyqxmd.com/read/29578107/clinical-features-and-management-of-acquired-resistance-to-pd-1-axis-inhibitors-in-26-patients-with-advanced-non-small-cell-lung-cancer
#3
Scott N Gettinger, Anna Wurtz, Sarah B Goldberg, David Rimm, Kurt Schalper, Susan Kaech, Paula Kavathas, Anne Chiang, Rogerio Lilenbaum, Daniel Zelterman, Katerina Politi, Roy S Herbst
INTRODUCTION: With expanding indications for programmed death 1 (PD-1) axis inhibitors in non-small cell lung cancer (NSCLC), acquired resistance (AR) to these therapies is increasingly being encountered. We sought to characterize clinical patterns of AR to PD-1 axis inhibitors in patients with advanced NSCLC, and evaluate subsequent outcome and management strategies for such patients. METHODS: Patients with NSCLC who developed AR to PD-1 axis inhibitor therapy initiated between December 2009 and February 2016 at one institution were identified and examined by clinical and radiographic features...
June 2018: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29449309/zeb1-zeb2-and-the-mir-200-family-form-a-counterregulatory-network-to-regulate-cd8-t-cell-fates
#4
Tianxia Guan, Claudia X Dominguez, Robert A Amezquita, Brian J Laidlaw, Jijun Cheng, Jorge Henao-Mejia, Adam Williams, Richard A Flavell, Jun Lu, Susan M Kaech
Long-term immunity depends partly on the establishment of memory CD8+ T cells. We identified a counterregulatory network between the homologous transcription factors ZEB1 and ZEB2 and the miR-200 microRNA family, which modulates effector CD8+ T cell fates. Unexpectedly, Zeb1 and Zeb2 had reciprocal expression patterns and were functionally uncoupled in CD8+ T cells. ZEB2 promoted terminal differentiation, whereas ZEB1 was critical for memory T cell survival and function. Interestingly, the transforming growth factor β (TGF-β) and miR-200 family members, which counterregulate the coordinated expression of Zeb1 and Zeb2 during the epithelial-to-mesenchymal transition, inversely regulated Zeb1 and Zeb2 expression in CD8+ T cells...
April 2, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29440270/correction-stat4-and-t-bet-control-follicular-helper-t-cell-development-in-viral-infections
#5
Jason S Weinstein, Brian J Laidlaw, Yisi Lu, Jessica K Wang, Vincent P Schulz, Ningcheng Li, Edward I Herman, Susan M Kaech, Patrick G Gallagher, Joe Craft
No abstract text is available yet for this article.
March 5, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29436395/myeloid-targeted-immunotherapies-act-in-synergy-to-induce-inflammation-and-antitumor-immunity
#6
Curtis J Perry, Andrés R Muñoz-Rojas, Katrina M Meeth, Laura N Kellman, Robert A Amezquita, Durga Thakral, Victor Y Du, Jake Xiao Wang, William Damsky, Alexandra L Kuhlmann, Joel W Sher, Marcus Bosenberg, Kathryn Miller-Jensen, Susan M Kaech
Eliciting effective antitumor immune responses in patients who fail checkpoint inhibitor therapy is a critical challenge in cancer immunotherapy, and in such patients, tumor-associated myeloid cells and macrophages (TAMs) are promising therapeutic targets. We demonstrate in an autochthonous, poorly immunogenic mouse model of melanoma that combination therapy with an agonistic anti-CD40 mAb and CSF-1R inhibitor potently suppressed tumor growth. Microwell assays to measure multiplex protein secretion by single cells identified that untreated tumors have distinct TAM subpopulations secreting MMP9 or cosecreting CCL17/22, characteristic of an M2-like state...
March 5, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29348504/trials-and-tribble-ations-of-tissue-t-rm-cells
#7
Jun Siong Low, Susan M Kaech
No abstract text is available yet for this article.
February 2018: Nature Immunology
https://www.readbyqxmd.com/read/29212666/stat4-and-t-bet-control-follicular-helper-t-cell-development-in-viral-infections
#8
Jason S Weinstein, Brian J Laidlaw, Yisi Lu, Jessica K Wang, Vincent P Schulz, Ningcheng Li, Edward I Herman, Susan M Kaech, Patrick G Gallagher, Joe Craft
Follicular helper T (Tfh) cells promote germinal center (GC) B cell survival and proliferation and guide their differentiation and immunoglobulin isotype switching by delivering contact-dependent and soluble factors, including IL-21, IL-4, IL-9, and IFN-γ. IL-21 and IFN-γ are coexpressed by Tfh cells during viral infections, but transcriptional regulation of these cytokines is not completely understood. In this study, we show that the T helper type 1 cell (Th1 cell) transcriptional regulators T-bet and STAT4 are coexpressed with Bcl6 in Tfh cells after acute viral infection, with a temporal decline in T-bet in the waning response...
January 2, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29054998/interleukin-10-from-cd4-follicular-regulatory-t-cells-promotes-the-germinal-center-response
#9
Brian J Laidlaw, Yisi Lu, Robert A Amezquita, Jason S Weinstein, Jason A Vander Heiden, Namita T Gupta, Steven H Kleinstein, Susan M Kaech, Joe Craft
CD4+ follicular regulatory T (Tfr ) cells suppress B cell responses through modulation of follicular helper T (Tfh ) cells and germinal center (GC) development. We found that Tfr cells can also promote the GC response through provision of interleukin-10 (IL-10) after acute infection with lymphocytic choriomeningitis virus (LCMV). Sensing of IL-10 by B cells was necessary for optimal development of the GC response. GC B cells formed in the absence of Treg cell-derived IL-10 displayed an altered dark zone state and decreased expression of the transcription factor Forkhead box protein 1 (FOXO1)...
October 20, 2017: Science Immunology
https://www.readbyqxmd.com/read/29025772/impaired-hla-class-i-antigen-processing-and-presentation-as-a-mechanism-of-acquired-resistance-to-immune-checkpoint-inhibitors-in-lung-cancer
#10
Scott Gettinger, Jungmin Choi, Katherine Hastings, Anna Truini, Ila Datar, Ryan Sowell, Anna Wurtz, Weilai Dong, Guoping Cai, Mary Ann Melnick, Victor Y Du, Joseph Schlessinger, Sarah B Goldberg, Anne Chiang, Miguel F Sanmamed, Ignacio Melero, Jackeline Agorreta, Luis M Montuenga, Richard Lifton, Soldano Ferrone, Paula Kavathas, David L Rimm, Susan M Kaech, Kurt Schalper, Roy S Herbst, Katerina Politi
Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy-number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell-surface HLA Class I expression in the tumor and a matched patient-derived xenograft (PDX)...
December 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28894184/il-7-plays-a-critical-role-for-the-homeostasis-of-allergen-specific-memory-cd4-t-cells-in-the-lung-and-airways
#11
Seung-Min Yeon, Lea Halim, Anmol Chandele, Curtis J Perry, Sang Hoon Kim, Sun-Uk Kim, Youngjoo Byun, Soon Hong Yuk, Susan M Kaech, Yong Woo Jung
Memory T cells respond rapidly to repeated antigen exposure and can maintain their population for extended periods through self-renewal. These characteristics of memory T cells have mainly been studied during viral infections, whereas their existence and functions in allergic diseases have been studied incompletely. Since allergic patients can suffer repeated relapses caused by intermittent allergen exposure, we hypothesized that allergen- specific memory Th2 cells are present and the factors necessary for the maintenance of these cells are provided by the lung and airways...
September 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28827827/transient-expression-of-zbtb32-in-anti-viral-cd8-t-cells-limits-the-magnitude-of-the-effector-response-and-the-generation-of-memory
#12
Hyun Mu Shin, Varun N Kapoor, Gwanghun Kim, Peng Li, Hang-Rae Kim, M Suresh, Susan M Kaech, E John Wherry, Liisa K Selin, Warren J Leonard, Raymond M Welsh, Leslie J Berg
Virus infections induce CD8+ T cell responses comprised of a large population of terminal effector cells and a smaller subset of long-lived memory cells. The transcription factors regulating the relative expansion versus the long-term survival potential of anti-viral CD8+ T cells are not completely understood. We identified ZBTB32 as a transcription factor that is transiently expressed in effector CD8+ T cells. After acute virus infection, CD8+ T cells deficient in ZBTB32 showed enhanced virus-specific CD8+ T cell responses, and generated increased numbers of virus-specific memory cells; in contrast, persistent expression of ZBTB32 suppressed memory cell formation...
August 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28713870/il-10-induces-a-stat3-dependent-autoregulatory-loop-in-t-h-2-cells-that-promotes-blimp-1-restriction-of-cell-expansion-via-antagonism-of-stat5-target-genes
#13
Amanda C Poholek, Dragana Jankovic, Alejandro V Villarino, Franziska Petermann, Angela Hettinga, Dror S Shouval, Scott B Snapper, Susan M Kaech, Stephen R Brooks, Golnaz Vahedi, Alan Sher, Yuka Kanno, John J O'Shea
Blimp-1 expression in T cells extinguishes the fate of T follicular helper cells, drives terminal differentiation, and limits autoimmunity. Although various factors have been described to control Blimp-1 expression in T cells, little is known about what regulates Blimp-1 expression in T helper 2 (TH 2) cells and the molecular basis of its actions. We report that signal transducer and activator of transcription 3 (STAT3) unexpectedly played a critical role in regulating Blimp-1 in TH 2 cells. Furthermore, we found that the cytokine interleukin-10 (IL-10) acted directly on TH 2 cells and was necessary and sufficient to induce optimal Blimp-1 expression through STAT3...
October 2016: Science Immunology
https://www.readbyqxmd.com/read/28701508/prdm1-regulates-thymic-epithelial-function-to-prevent-autoimmunity
#14
Natalie A Roberts, Brian D Adams, Nicholas I McCarthy, Reuben M Tooze, Sonia M Parnell, Graham Anderson, Susan M Kaech, Valerie Horsley
Autoimmunity is largely prevented by medullary thymic epithelial cells (TECs) through their expression and presentation of tissue-specific Ags to developing thymocytes, resulting in deletion of self-reactive T cells and supporting regulatory T cell development. The transcription factor Prdm1 has been implicated in autoimmune diseases in humans through genome-wide association studies and in mice using cell type-specific deletion of Prdm1 in T and dendritic cells. In this article, we demonstrate that Prdm1 functions in TECs to prevent autoimmunity in mice...
August 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28475890/metabolic-instruction-of-immunity
#15
REVIEW
Michael D Buck, Ryan T Sowell, Susan M Kaech, Erika L Pearce
Choices have consequences. Immune cells survey and migrate throughout the body and sometimes take residence in niche environments with distinct communities of cells, extracellular matrix, and nutrients that may differ from those in which they matured. Imbedded in immune cell physiology are metabolic pathways and metabolites that not only provide energy and substrates for growth and survival, but also instruct effector functions, differentiation, and gene expression. This review of immunometabolism will reference the most recent literature to cover the choices that environments impose on the metabolism and function of immune cells and highlight their consequences during homeostasis and disease...
May 4, 2017: Cell
https://www.readbyqxmd.com/read/28458087/reenergizing-t-cell-anti-tumor-immunity-by-harnessing-immunometabolic-checkpoints-and-machineries
#16
REVIEW
Ping-Chih Ho, Susan M Kaech
T cells patrol our bodies preventing pathogenic infections and malignant cell outgrowth. However, T cells must be properly controlled because aberrant or persistent T cell responses can damage tissues and contribute to autoimmune diseases and other chronic inflammatory diseases including metabolic syndrome. One regulatory mechanism utilized in immune cells is immunometabolic regulation, which ensures immune cells properly respond to systemic and peripheral metabolic cues. Recent work has suggested that deregulated metabolism in tumor cells creates a microenvironmental barrier for mounting effective anti-tumor immune responses...
June 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28410989/polycomb-repressive-complex-2-mediated-chromatin-repression-guides-effector-cd8-t-cell-terminal-differentiation-and-loss-of-multipotency
#17
Simon M Gray, Robert A Amezquita, Tianxia Guan, Steven H Kleinstein, Susan M Kaech
Understanding immunological memory formation depends on elucidating how multipotent memory precursor (MP) cells maintain developmental plasticity and longevity to provide long-term immunity while other effector cells develop into terminally differentiated effector (TE) cells with limited survival. Profiling active (H3K27ac) and repressed (H3K27me3) chromatin in naive, MP, and TE CD8+ T cells during viral infection revealed increased H3K27me3 deposition at numerous pro-memory and pro-survival genes in TE relative to MP cells, indicative of fate restriction, but permissive chromatin at both pro-memory and pro-effector genes in MP cells, indicative of multipotency...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28379630/uv-induced-somatic-mutations-elicit-a-functional-t-cell-response-in-the-yummer1-7-mouse-melanoma-model
#18
Jake Wang, Curtis J Perry, Katrina Meeth, Durga Thakral, William Damsky, Goran Micevic, Susan Kaech, Kim Blenman, Marcus Bosenberg
Human melanomas exhibit relatively high somatic mutation burden compared to other malignancies. These somatic mutations may produce neoantigens that are recognized by the immune system, leading to an antitumor response. By irradiating a parental mouse melanoma cell line carrying three driver mutations with UVB and expanding a single-cell clone, we generated a mutagenized model that exhibits high somatic mutation burden. When inoculated at low cell numbers in immunocompetent C57BL/6J mice, YUMMER1.7 (Yale University Mouse Melanoma Exposed to Radiation) regresses after a brief period of growth...
July 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/28295222/traf3-cyld-mutations-identify-a-distinct-subset-of-human-papillomavirus-associated-head-and-neck-squamous-cell-carcinoma
#19
Michael Hajek, Andrew Sewell, Susan Kaech, Barbara Burtness, Wendell G Yarbrough, Natalia Issaeva
BACKGROUND: The incidence of human papillomavirus (HPV)-associated (HPV-positive) head and neck squamous cell carcinoma (HNSCC) of the oropharynx has dramatically increased over the last decade and continues to rise. Newly diagnosed HPV-positive HNSCCs in the United States currently outnumber any other HPV-associated cancers, including cervical cancer. Despite introduction of the HPV vaccine, the epidemic of HPV-positive HNSCC is expected to continue for approximately 60 years. Compared with patients who have tobacco-associated HNSCC, those who have HPV-positive HNSCC have better overall survival and response to treatment...
May 15, 2017: Cancer
https://www.readbyqxmd.com/read/28225757/immunology-the-chronicles-of-t-cell-exhaustion
#20
COMMENT
Robert A Amezquita, Susan M Kaech
No abstract text is available yet for this article.
March 9, 2017: Nature
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