PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response?
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TLDR
Improve understanding of the efficacy of PD-1/PD-L1 blockade immunotherapy, as well as enhance the development of therapeutic strategies to overcome the resistance mechanisms and unleash the antitumor immune response to combat cancer.Abstract:
PD-1-PD-L1 interaction is known to drive T cell dysfunction, which can be blocked by anti-PD-1/PD-L1 antibodies. However, studies have also shown that the function of the PD-1-PD-L1 axis is affected by the complex immunologic regulation network, and some CD8+ T cells can enter an irreversible dysfunctional state that cannot be rescued by PD-1/PD-L1 blockade. In most advanced cancers, except Hodgkin lymphoma (which has high PD-L1/L2 expression) and melanoma (which has high tumor mutational burden), the objective response rate with anti-PD-1/PD-L1 monotherapy is only ~20%, and immune-related toxicities and hyperprogression can occur in a small subset of patients during PD-1/PD-L1 blockade therapy. The lack of efficacy in up to 80% of patients was not necessarily associated with negative PD-1 and PD-L1 expression, suggesting that the roles of PD-1/PD-L1 in immune suppression and the mechanisms of action of antibodies remain to be better defined. In addition, important immune regulatory mechanisms within or outside of the PD-1/PD-L1 network need to be discovered and targeted to increase the response rate and to reduce the toxicities of immune checkpoint blockade therapies. This paper reviews the major functional and clinical studies of PD-1/PD-L1, including those with discrepancies in the pathologic and biomarker role of PD-1 and PD-L1 and the effectiveness of PD-1/PD-L1 blockade. The goal is to improve understanding of the efficacy of PD-1/PD-L1 blockade immunotherapy, as well as enhance the development of therapeutic strategies to overcome the resistance mechanisms and unleash the antitumor immune response to combat cancer.read more
Citations
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Journal ArticleDOI
Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors
TL;DR: Biomarkers reflecting tumor immune microenvironment and tumor cell intrinsic features, such as PD-L1 expression, density of tumor infiltrating lymphocyte (TIL), tumor mutational burden, and mismatch-repair (MMR) deficiency, have been noticed to associate with treatment effect of anti-PD-1/anti-PD.
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Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis.
Xian Shen,Bin Zhao +1 more
TL;DR: It is suggested that PD-L1 expression status alone is insufficient in determining which patients should be offered PD-1 or PD- L1 blockade therapy, which is a preferable treatment option over conventional therapy for both patients that are PD- l1 positive and PD-l1 negative.
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PD-1/PD-L1 pathway: Basic biology and role in cancer immunotherapy
Arash Salmaninejad,Arash Salmaninejad,Saeed Farajzadeh Valilou,Arezoo Gowhari Shabgah,Saeed Aslani,Malihe Alimardani,Alireza Pasdar,Alireza Pasdar,Amirhossein Sahebkar +8 more
TL;DR: The promotion of cancer immunotherapy targeting PD‐1 immunoinhibitory pathway is discussed and attempts to identify novel and well‐suited predictive biomarkers are sensed.
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RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance (IRC5P.465)
Yanping Xiao,Sanhong Yu,Baogong Zhu,Denis Bedoret,Xia Bu,Loise M. Francisco,Ping Hua,Jonathan S. Duke-Cohan,Dale T. Umetsu,Arlene H. Sharpe,Arlene H. Sharpe,Rosemarie H. DeKruyff,Gordon J. Freeman +12 more
TL;DR: In this article, the authors showed that PD-L2 binding to repulsive guidance molecule b (RGMb) significantly impaired the development of respiratory tolerance by interfering with the initial T cell expansion required for respiratory tolerance.
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ATR kinase inhibitor AZD6738 potentiates CD8+ T cell–dependent antitumor activity following radiation
Frank P. Vendetti,Pooja Karukonda,David A. Clump,Troy P. Teo,R. Lalonde,Katriana Nugent,Matthew Ballew,Brian F. Kiesel,Jan H. Beumer,Saumendra N. Sarkar,Thomas P. Conrads,Mark J. O'Connor,Robert L. Ferris,Phuoc T. Tran,Greg M. Delgoffe,Christopher J. Bakkenist +15 more
TL;DR: It is shown that the ATR kinase inhibitor AZD6738 combines with conformal radiation therapy to attenuate radiation-induced CD8+ T cell exhaustion and potentiate T cell activity in mouse models of Kras-mutant cancer.
References
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TL;DR: Subcategorizing MBCs on the basis of their expression of CD80 and PD-L2, independently of isotype, identified MBC subsets with distinct functions upon rechallenge and supported both the identity and function of these distinct MBC types.
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