Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade.
Pei Ling Chen,Whijae Roh,Alexandre Reuben,Zachary A. Cooper,Christine N. Spencer,Peter A. Prieto,John P. Miller,Roland L. Bassett,Vancheswaran Gopalakrishnan,Khalida Wani,Mariana Petaccia de Macedo,Jacob Austin-Breneman,Hong Jiang,Qing Chang,Sangeetha M. Reddy,Wei Shen Chen,Michael T. Tetzlaff,Russell J. Broaddus,Michael A. Davies,Jeffrey E. Gershenwald,Lauren E. Haydu,Alexander J. Lazar,Sapna Pradyuman Patel,Patrick Hwu,Wen-Jen Hwu,Adi Diab,Isabella C. Glitza,Scott E. Woodman,Luis M Vence,Ignacio I. Wistuba,Rodabe N. Amaria,Lawrence N. Kwong,Victor G. Prieto,R. Eric Davis,Wencai Ma,Willem W. Overwijk,Arlene H. Sharpe,Jianhua Hu,P. Andrew Futreal,Jorge Blando,Padmanee Sharma,James P. Allison,Lynda Chin,Jennifer A. Wargo +43 more
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TLDR
It is demonstrated that adaptive immune signatures in tumor biopsy samples obtained early during the course of treatment are highly predictive of response to immune checkpoint blockade and also demonstrate differential effects on the tumor microenvironment induced by CTLA4 and PD-1 blockade.Abstract:
Immune checkpoint blockade represents a major breakthrough in cancer therapy, however responses are not universal. Genomic and immune features in pre-treatment tumor biopsies have been reported to correlate with response in patients with melanoma and other cancers, but robust biomarkers have not been identified. We studied a cohort of metastatic melanoma patients initially treated with cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockade (n=53) followed by programmed death-1 (PD-1) blockade at progression (n=46), and analyzed immune signatures in longitudinal tissue samples collected at multiple time points during therapy. In these studies, we demonstrate that adaptive immune signatures in tumor biopsy samples obtained early during the course of treatment are highly predictive of response to immune checkpoint blockade, and also demonstrate differential effects on the tumor microenvironment induced by CTLA-4 and PD-1 blockade. Importantly, potential mechanisms of therapeutic resistance to immune checkpoint blockade were also identified. Significance: These studies demonstrate that adaptive immune signatures in early on-treatment tumor biopsies are predictive of response to checkpoint blockade, and yield insight into mechanisms of therapeutic resistance. These concepts have far-reaching implications in this age of precision medicine, and should be explored in immune checkpoint blockade treatment across cancer types.read more
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Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy.
TL;DR: As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.
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Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients
Vancheswaran Gopalakrishnan,Vancheswaran Gopalakrishnan,Christine N. Spencer,Christine N. Spencer,Luigi Nezi,Alexandre Reuben,Miles C. Andrews,Tatiana Karpinets,Peter A. Prieto,D. Vicente,K. Hoffman,Spencer C. Wei,Alexandria P. Cogdill,Li Zhao,Courtney W. Hudgens,Diane S. Hutchinson,T. Manzo,M. Petaccia de Macedo,Tiziana Cotechini,T. Kumar,Wei Shen Chen,Sangeetha M. Reddy,R. Szczepaniak Sloane,Jessica Galloway-Peña,Hong Jiang,P. L. Chen,Elizabeth J. Shpall,Katayoun Rezvani,Amin M. Alousi,Roy F. Chemaly,Samuel A. Shelburne,Luis M Vence,Pablo C. Okhuysen,V. B. Jensen,Alton G. Swennes,Florencia McAllister,E. Marcelo Riquelme Sanchez,Yu Zhang,Laurence Zitvogel,Nicolas Pons,Jacob Austin-Breneman,Lauren E. Haydu,Elizabeth M. Burton,J. M. Gardner,E. Sirmans,Jing Shan Hu,Alexander J. Lazar,Takahiro Tsujikawa,Adi Diab,Hussein Abdul-Hassan Tawbi,Isabella C. Glitza,Wen-Jen Hwu,Sapna Pradyuman Patel,Scott E. Woodman,Rodabe N. Amaria,Michael A. Davies,Jeffrey E. Gershenwald,Patrick Hwu,J. E. Lee,Jianhua Zhang,Lisa M. Coussens,Zachary A. Cooper,P.A. Futreal,Carrie R. Daniel,Carrie R. Daniel,Nadim J. Ajami,Joseph F. Petrosino,Michael T. Tetzlaff,Pradeep Sharma,James P. Allison,Robert R. Jenq,Jennifer A. Wargo +71 more
TL;DR: Examination of the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients.
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Determining cell type abundance and expression from bulk tissues with digital cytometry.
Aaron M. Newman,Chloé B. Steen,Chloé B. Steen,Chih Long Liu,Andrew J. Gentles,Aadel A. Chaudhuri,Florian Scherer,Michael S. Khodadoust,Mohammad Shahrokh Esfahani,Bogdan A. Luca,David F. Steiner,Maximilian Diehn,Ash A. Alizadeh +12 more
TL;DR: The utility of CIBERSORTx is evaluated in multiple tumor types, including melanoma, where single-cell reference profiles were used to dissect bulk clinical specimens, revealing cell-type-specific phenotypic states linked to distinct driver mutations and response to immune checkpoint blockade.
Journal ArticleDOI
The immune contexture in cancer prognosis and treatment
Wolf H. Fridman,Laurence Zitvogel,Catherine Sautès-Fridman,Catherine Sautès-Fridman,Catherine Sautès-Fridman,Guido Kroemer +5 more
TL;DR: The immune contexture, which is determined by the density, composition, functional state and organization of the leukocyte infiltrate of the tumour, can yield information that is relevant to prognosis, prediction of a treatment response and various other pharmacodynamic parameters.
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Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab.
Nadeem Riaz,Jonathan J. Havel,Vladimir Makarov,Alexis Desrichard,Walter J. Urba,Jennifer S. Sims,F. Stephen Hodi,Salvador Martín-Algarra,Rajarsi Mandal,William H. Sharfman,Shailender Bhatia,Wen-Jen Hwu,Thomas F. Gajewski,Craig L. Slingluff,Diego Chowell,Sviatoslav M. Kendall,Han Chang,Rachna Shah,Fengshen Kuo,Luc G. T. Morris,John-William Sidhom,Jonathan P. Schneck,Christine Horak,Nils Weinhold,Timothy A. Chan +24 more
TL;DR: Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action and reveal expansion of T cell clones in the setting of neoantigen loss.
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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.
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