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Filename: controllers/Detail.php
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File: /var/www/html/index.php
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Targeting the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway with immunotherapy has revolutionized the treatment of many cancers. Somatic tumor mutational burden (TMB) and T-cell-inflamed gene expression profile (GEP) are clinically validated pan-tumor genomic biomarkers that can predict responsiveness to anti-PD-1/PD-L1 monotherapy in many tumor types. We analyzed the association between these biomarkers and the efficacy of PD-1 inhibitor in 11 commonly used preclinical syngeneic tumor mouse models using murinized rat anti-mouse PD-1 DX400 antibody muDX400, a surrogate for pembrolizumab. Response to muDX400 treatment was broadly classified into three categories: highly responsive, partially responsive, and intrinsically resistant to therapy. Molecular and cellular profiling validated differences in immune cell infiltration and activation in the tumor microenvironment of muDX400-responsive tumors. Baseline and on-treatment genomic analysis showed an association between TMB, murine T-cell-inflamed gene expression profile (murine-GEP), and response to muDX400 treatment. We extended our analysis to investigate a canonical set of cancer and immune biology-related gene signatures, including signatures of angiogenesis, myeloid-derived suppressor cells, and stromal/epithelial-to-mesenchymal transition/TGFβ biology previously shown to be inversely associated with the clinical efficacy of immune checkpoint blockade. Finally, we evaluated the association between murine-GEP and preclinical efficacy with standard-of-care chemotherapy or antiangiogenic agents that previously demonstrated promising clinical activity, in combination with muDX400. Our profiling studies begin to elucidate the underlying biological mechanisms of response and resistance to PD-1/PD-L1 blockade represented by these models, thereby providing insight into which models are most appropriate for the evaluation of orthogonal combination strategies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377732 | PMC |
http://dx.doi.org/10.1158/1535-7163.MCT-21-0561 | DOI Listing |
Oncoimmunology
December 2025
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Regulatory T cells (Tregs) contribute significantly to the immunosuppressive nature of the tumor microenvironment which is a main barrier for immunotherapies of solid cancers. Reducing Treg numbers enhances anti-tumor immune responses but current depletion strategies also impair effector T cells (Teffs), potentially leading to reduced anti-tumor immunity and/or autoimmune diseases. CD137 has been identified as the most differentially expressed gene between peripheral Tregs and intratumoral Tregs in virtually all solid cancers.
View Article and Find Full Text PDFNat Biomed Eng
December 2024
Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Resistance to chimaeric antigen receptor (CAR) T cell therapy develops through multiple mechanisms, most notably antigen loss and tumour-induced immune suppression. It has been suggested that T cells expressing multiple CARs may overcome the resistance of tumours and that T cells expressing receptors that switch inhibitory immune-checkpoint signals into costimulatory signals may enhance the activity of the T cells in the tumour microenvironment. However, engineering multiple features into a single T cell product is difficult because of the transgene-packaging constraints of current gene-delivery vectors.
View Article and Find Full Text PDFClin Exp Metastasis
December 2024
Christopher S. Bond Life Sciences Center 540F, University of Missouri, 1201 E Rollins, Columbia, MO, 65211, USA.
Copper promotes tumor growth and metastasis through a variety of mechanisms, most notably as a cofactor within the lysyl oxidase (LOX) family of secreted cuproenzymes. Members of this family, which include LOX and LOX-like enzymes LOXL1-4, catalyze the copper-dependent crosslinking of collagens and elastin within the extracellular matrix (ECM). Elevated LOX expression is associated with higher incidence and worse prognosis in multiple cancers, including colorectal, breast, pancreatic, and head and neck.
View Article and Find Full Text PDFMedComm (2020)
January 2025
Agonists of the stimulator of interferon genes (STING) pathway are increasingly being recognized as a promising new approach in the treatment of cancer. Although progress in clinical trials for STING agonists in antitumor applications has been slow, there is still an urgent need for developing new potent STING agonists with versatile potential applications. Herein, we developed and identified a non-nucleotide STING agonist called DW18343.
View Article and Find Full Text PDFImmunology
December 2024
Department of Hepatobiliary Surgery, Municipal Hospital Affiliated to Taizhou University, Taizhou, Zhejiang, China.
This study attempted to identify the relevant pathways involved in autophagy activation of pancreatic cancer and explore the mechanisms underlying immune evasion. Western blot (WB) was used to detect the expression of ITGB4, BNIP3, autophagy-related proteins and MHC-I. Co-immunoprecipitation (Co-IP) was used to verify the binding mode of ITGB4 and BNIP3.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!