Journal ArticleDOI
The diverse functions of the PD1 inhibitory pathway.
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TLDR
The diverse roles of the PD1 pathway in regulating immune responses are discussed and how this knowledge can improve cancer immunotherapy as well as restore and/or maintain tolerance during autoimmunity and transplantation.Abstract:
T cell activation is a highly regulated process involving peptide-MHC engagement of the T cell receptor and positive costimulatory signals. Upon activation, coinhibitory 'checkpoints', including programmed cell death protein 1 (PD1), become induced to regulate T cells. PD1 has an essential role in balancing protective immunity and immunopathology, homeostasis and tolerance. However, during responses to chronic pathogens and tumours, PD1 expression can limit protective immunity. Recently developed PD1 pathway inhibitors have revolutionized cancer treatment for some patients, but the majority of patients do not show complete responses, and adverse events have been noted. This Review discusses the diverse roles of the PD1 pathway in regulating immune responses and how this knowledge can improve cancer immunotherapy as well as restore and/or maintain tolerance during autoimmunity and transplantation.read more
Citations
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Journal ArticleDOI
Regulation and Function of the PD-L1 Checkpoint
TL;DR: The roles of the PD-1-PD-L1 axis in cancer is reviewed, focusing on recent findings on the mechanisms that regulate PD-L 1 expression at the transcriptional, posttranscriptional, and protein level, to inform the design of more precise and effective cancer immune checkpoint therapies.
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Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy
TL;DR: The current understanding of the physical, cellular, and molecular mechanisms by which the pathological tumor ECM affects the efficiency of radio-, chemo-, and immunotherapy is highlighted.
Journal ArticleDOI
LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade
Wanqiang Sheng,Wanqiang Sheng,Martin W. LaFleur,Thao H. Nguyen,Sujun Chen,Sujun Chen,Ankur Chakravarthy,Ankur Chakravarthy,Jake Conway,Ying Li,Hao Chen,Hao Chen,Henry Yang,Pang-Hung Hsu,Eliezer M. Van Allen,Gordon J. Freeman,Daniel D. De Carvalho,Daniel D. De Carvalho,Housheng Hansen He,Housheng Hansen He,Arlene H. Sharpe,Arlene H. Sharpe,Yang Shi,Yang Shi +23 more
TL;DR: It is demonstrated that ablation of the histone demethylase LSD1 in cancer cells increases repetitive element expression, including endogenous retroviral elements (ERVs), and decreases expression of RNA-induced silencing complex (RISC) components.
Journal ArticleDOI
Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion
TL;DR: In this paper, the authors review the tumour-derived factors modulating DC function, and summarize evidence of immune evasion by means of quantitative modulation or qualitative alteration of the antigen repertoire presented on tumours.
Journal ArticleDOI
Intratumoral Activity of the CXCR3 Chemokine System Is Required for the Efficacy of Anti-PD-1 Therapy.
Melvyn T. Chow,Aleksandra J. Ozga,Rachel L. Servis,Dennie T. Frederick,Jennifer A. Lo,David E. Fisher,Gordon J. Freeman,Genevieve M. Boland,Andrew D. Luster +8 more
TL;DR: The data suggest that the CXCR3 chemokines system is a biomarker for sensitivity to PD-1 blockade and that augmenting the intratumoral function of this chemokine system could improve clinical outcomes.
References
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Journal ArticleDOI
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
Suzanne L. Topalian,F. Stephen Hodi,Julie R. Brahmer,Scott N. Gettinger,David Smith,David F. McDermott,John D. Powderly,Richard D. Carvajal,Jeffrey A. Sosman,Michael B. Atkins,Philip D. Leming,David R. Spigel,Scott J. Antonia,Leora Horn,Charles G. Drake,Drew M. Pardoll,Lieping Chen,William H. Sharfman,Robert A. Anders,Janis M. Taube,Tracee L. McMiller,Haiying Xu,Alan J. Korman,Maria Jure-Kunkel,Shruti Agrawal,Dan McDonald,Georgia Kollia,Ashok Kumar Gupta,Jon M. Wigginton,Mario Sznol +29 more
TL;DR: Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use.
Journal ArticleDOI
The blockade of immune checkpoints in cancer immunotherapy
TL;DR: Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
Journal ArticleDOI
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Dung T. Le,Jennifer N. Uram,Hao Wang,Bjarne Bartlett,Holly Kemberling,Aleksandra Eyring,Andrew D. Skora,Brandon Luber,Nilofer S. Azad,Daniel A. Laheru,Barbara A. Biedrzycki,Ross C. Donehower,Atif Zaheer,George A. Fisher,Todd S. Crocenzi,James J. Lee,Steven M. Duffy,Richard M. Goldberg,Richard M. Goldberg,Albert de la Chapelle,Albert de la Chapelle,Minori Koshiji,Feriyl Bhaijee,Thomas Huebner,Ralph H. Hruban,Laura D. Wood,Nathan Cuka,Drew M. Pardoll,Nickolas Papadopoulos,Kenneth W. Kinzler,Shibin Zhou,Toby C. Cornish,Janis M. Taube,Robert A. Anders,James R. Eshleman,Bert Vogelstein,Luis A. Diaz +36 more
TL;DR: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab, and high somatic mutation loads were associated with prolonged progression-free survival.
Journal ArticleDOI
Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer
Julie R. Brahmer,Scott S. Tykodi,Scott S. Tykodi,Laura Q.M. Chow,Wen-Jen Hwu,Suzanne L. Topalian,Patrick Hwu,Charles G. Drake,Luis H. Camacho,John S. Kauh,Kunle Odunsi,Henry C. Pitot,Omid Hamid,Shailender Bhatia,Renato G. Martins,Keith D. Eaton,Shuming Chen,Theresa M. Salay,Suresh Alaparthy,Joseph F. Grosso,Alan J. Korman,Susan M. Parker,Shruti Agrawal,Stacie M. Goldberg,Drew M. Pardoll,Ashok Kumar Gupta,Jon M. Wigginton +26 more
TL;DR: Antibody-mediated blockade of PD-L1 induced durable tumor regression and prolonged stabilization of disease in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer.
Journal ArticleDOI
Cancer Genome Landscapes
Bert Vogelstein,Nickolas Papadopoulos,Victor E. Velculescu,Shibin Zhou,Luis A. Diaz,Kenneth W. Kinzler +5 more
TL;DR: This work has revealed the genomic landscapes of common forms of human cancer, which consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of "hills" (Genes altered infrequently).
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