Targeting DDR2 enhances tumor response to anti–PD-1 immunotherapy
Megan M. Tu,Francis Y. Lee,Robert T. Jones,Abigail K. Kimball,Elizabeth Saravia,Robert F. Graziano,Brianne M. Coleman,Krista Menard,Jun Yan,Erin Michaud,Han Chang,Hany A. Abdel-Hafiz,Andrii I. Rozhok,Jason E. Duex,Neeraj Agarwal,Ana Chauca-Diaz,Linda K. Johnson,Terry L. Ng,John C. Cambier,Eric T. Clambey,James C. Costello,Alan J. Korman,Dan Theodorescu +22 more
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TLDR
This work shows that DDR2 depletion increases sensitivity to anti–PD-1 treatment compared to monotherapy, and provides strong scientific rationale for targeting DDR2 in combination with PD-1 inhibitors.Abstract:
While a fraction of cancer patients treated with anti-PD-1 show durable therapeutic responses, most remain unresponsive, highlighting the need to better understand and improve these therapies. Using an in vivo screening approach with a customized shRNA pooled library, we identified DDR2 as a leading target for the enhancement of response to anti-PD-1 immunotherapy. Using isogenic in vivo murine models across five different tumor histologies-bladder, breast, colon, sarcoma, and melanoma-we show that DDR2 depletion increases sensitivity to anti-PD-1 treatment compared to monotherapy. Combination treatment of tumor-bearing mice with anti-PD-1 and dasatinib, a tyrosine kinase inhibitor of DDR2, led to tumor load reduction. RNA-seq and CyTOF analysis revealed higher CD8+ T cell populations in tumors with DDR2 depletion and those treated with dasatinib when either was combined with anti-PD-1 treatment. Our work provides strong scientific rationale for targeting DDR2 in combination with PD-1 inhibitors.read more
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The matrix in cancer.
TL;DR: This Review touches on many of the facets of matrix biology in solid cancers, including breast, pancreatic and lung cancer, with the aim of highlighting some of the emerging interactions of the matrix and influences that the matrix has on tumour onset, progression and metastatic dissemination, before summarizing the ongoing work in the field aimed at developing therapies to co-target the matrix in cancer and cancer metastasis.
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Advances in bladder cancer biology and therapy
TL;DR: Recent developments in the molecular and translational aspects of bladder cancer biology are examined and their current or potential future clinical applications in the management of bladdercancer are discussed.
Journal ArticleDOI
Inhibition of the CCL2 receptor, CCR2, enhances tumor response to immune checkpoint therapy.
Megan M. Tu,Hany A Abdel-Hafiz,Robert T. Jones,Annie Jean,Katelyn J Hoff,Jason E. Duex,Ana Chauca-Diaz,James C. Costello,Garrett M. Dancik,Beth A. Jirón Tamburini,Bogdan Czerniak,Jonathan Kaye,Dan Theodorescu +12 more
TL;DR: It is shown across multiple murine tumor and metastasis models that CCR2 antagonism in combination with anti- PD-1 therapy leads to sensitization and enhanced tumor response over anti-PD-1 monotherapy and that enhanced treatment response correlates with enhanced CD8 + T cell recruitment and activation and a concomitant decrease in CD4 + regulatory T cell.
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Collagen Kinase Receptors as Potential Therapeutic Targets in Metastatic Colon Cancer.
TL;DR: Recent findings on the metastatic role of the collagen receptors Discoidin Domain Receptors 1 and 2 (DDR1 and DDR2) in CRC are reviewed and the therapeutic value of targeting these receptor tyrosine kinases in this cancer is discussed.
Journal ArticleDOI
Determinants of Resistance to Checkpoint Inhibitors.
Linda Tran,Dan Theodorescu +1 more
TL;DR: There is a great need to further elucidate mechanisms of resistant disease and determine novel, effective, and tolerable combination therapies to enhance efficacy of ICIs.
References
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TL;DR: Burrows-Wheeler Alignment tool (BWA) is implemented, a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps.
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TL;DR: Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.
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TL;DR: The Gene Set Enrichment Analysis (GSEA) method as discussed by the authors focuses on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation.
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Bo Li,Colin N. Dewey +1 more
TL;DR: It is shown that accurate gene-level abundance estimates are best obtained with large numbers of short single-end reads, and estimates of the relative frequencies of isoforms within single genes may be improved through the use of paired- end reads, depending on the number of possible splice forms for each gene.
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A framework for variation discovery and genotyping using next-generation DNA sequencing data
Mark A. DePristo,Eric Banks,Ryan Poplin,Kiran V. Garimella,Jared Maguire,Christopher Hartl,Anthony A. Philippakis,Anthony A. Philippakis,Anthony A. Philippakis,Guillermo del Angel,Manuel A. Rivas,Manuel A. Rivas,Matt Hanna,Aaron McKenna,Timothy Fennell,Andrew Kernytsky,Andrey Sivachenko,Kristian Cibulskis,Stacey Gabriel,David Altshuler,David Altshuler,Mark J. Daly,Mark J. Daly +22 more
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