Scientists showed that microparticle-mediated intratumoral delivery of NAMPT inhibitor GMX1778 induced specific immunological changes in the tumor microenvironment of murine glioblastoma, characterized by upregulation of immune checkpoint PD-L1, recruitment of CD3+, CD4+, and CD8+ T cells.
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Li, M., Kirtane, A. R., Kiyokawa, J., Nagashima, H., Lopes, A., Tirmizi, Z. A., Lee, C. K., Traverso, G., Cahill, D. P., & Wakimoto, H. (2020). Local targeting of NAD+ salvage pathway alters the immune tumor microenvironment and enhances checkpoint immunotherapy in glioblastoma. Cancer Research. https://doi.org/10.1158/0008-5472.CAN-20-1094 Cite
The authors describe a mechanism underlying the regulation of programmed cell death-1 (PD-1) at the mRNA level and demonstrated its impact on T-cell dysfunction. Transcriptomic analysis identified a correlation between transforming growth factor beta 1 and PDCD1 in clear cell renal cell carcinoma samples.
[Cancer Immunology Research]
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Wu, P., Geng, B., Chen, Q., Zhao, E., Liu, J., Sun, C., Zha, C., Shao, Y., You, B., Zhang, W., Li, L., Meng, X., Cai, J., & Li, X. (2020). Tumor cell-derived TGFβ1 Attenuates Antitumor Immune Activity of T cells via Regulation of PD-1 mRNA. Cancer Immunology Research. https://doi.org/10.1158/2326-6066.CIR-20-0113 Cite
Researchers studied 76 DAA-treated hepatitis C virus (HCV)-positive patients and 18 non-infected controls. Flow cytometry measured pretreatment frequencies of CD4+PD-1+, CD4+PD-1+Tim-3+ and CD8+PD-1+Tim-3+ T-cells and IL-10 levels measured by ELISA were significantly higher and CD4+PD-1−Tim-3− and CD8+PD-1−Tim-3− T-cells were significantly lower in patients than in controls.
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Decrease of T-cells exhaustion markers programmed cell death-1 and T-cell immunoglobulin and mucin domain-containing protein 3 and plasma IL-10 levels after successful treatment of chronic hepatitis C | Scientific Reports. (n.d.). Retrieved September 30, 2020, from https://www.nature.com/articles/s41598-020-73137-6 Cite
ALX Oncology announced it has entered into a clinical trial collaboration with Merck to evaluate the combination of ALX148, an investigational next generation CD47 blocker, and KEYTRUDA®, Merck’s anti-PD-1 therapy, for the treatment of patients with Head & Neck Squamous Cell Carcinoma.
The authors provide an overview of the recent advances on the mechanistic aspects of the PD-1 pathway and discuss the implications of these new discoveries and the gaps that remain to be filled.
The authors underline the failures and promises of immunotherapy in prostate cancer, summarizing the current state of art regarding cancer vaccines and immune checkpoint monoclonal antibodies, and discussing future research directions in this immunologically “cold” malignancy.
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To find cellular defects triggered by tumor exposure and associated PD-1 signaling, scientists established an ex vivo imaging approach to investigate the response of antigen-specific, activated effector CD8+ tumor-infiltrating lymphocytes after interaction with target tumor cells.
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The authors demonstrated that P2X7 was highly expressed in tumor-associated macrophages (TAMs) and that P2X7 deficiency impaired the “M2-like” polarization of TAMs via down-regulation of STAT6 and IRF4 phosphorylation both in vivo and in vitro.
[Cancer Immunology Research]
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SARS-CoV-2−specific CD8+ T cells recovered from convalescent COVID-19 patients had an atypically high prevalence of stem cell memory, central memory, and naïve phenotypes.
[Proceedings of the National Academy of Sciences of the United States of America]
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Habel, J. R., Nguyen, T. H. O., Sandt, C. E. van de, Juno, J. A., Chaurasia, P., Wragg, K., Koutsakos, M., Hensen, L., Jia, X., Chua, B., Zhang, W., Tan, H.-X., Flanagan, K. L., Doolan, D. L., Torresi, J., Chen, W., Wakim, L. M., Cheng, A. C., Doherty, P. C., … Kedzierska, K. (2020). Suboptimal SARS-CoV-2−specific CD8+ T cell response associated with the prominent HLA-A*02:01 phenotype. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.2015486117 Cite
Targeting IL-20 not only prolonged survival and attenuated PD-L1 expression in both murine models but also inhibited tumor growth and mitigated M2-like polarization in the orthotopic pancreatic ductal adenocarcinoma model.
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Investigators showed that selective blockade of TGF-β1 production by Tregs with antibodies against GARP:TGF-β1 complexes induced regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy.