Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non–small cell lung cancer

Gong, Bin; Kiyotani, Kazuma; Sakata, Seiji; Nagano, Seiji; Kumehara, Shun; Baba, Satoko; Besse, Benjamin; Yanagitani, Noriko; Friboulet, Luc; Nishio, Makoto; Takeuchi, Kengo; Kawamoto, Hiroshi; Fujita, Naoya; Katayama, Ryohei

doi:10.1084/jem.20180870

Cited by 191 publications

(174 citation statements)

References 42 publications

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“…Genomic or complementary DNA was extracted from the specimens, and the sequence in the ALK kinase domain was assessed using Sanger sequencing with the primers shown below. If resistant secondary mutations were not identified, the tumor samples were assessed for the presence of ALK independent resistance mechanisms, including EGFR, MET, KRAS or ALK mutation/amplification, cKIT amplification, overexpression of P‐gp or SCLC transformation, and cell lines, which are established from biopsy specimens through targeted next‐generation sequencing (with Agilent HaloPlex custom panel and Illumina MiSeq as described in our previous paper), using the Proteome Profiler Human Phospho‐RTK Array Kit (R&D Systems), immunoblot, immune‐histochemistry evaluation and histological diagnosis.…”

Section: Methodsmentioning

confidence: 99%

Drug resistance mechanisms in Japanese anaplastic lymphoma kinase‐positive non–small cell lung cancer and the clinical responses based on the resistant mechanisms

et al. 2020

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The treatment for anaplastic lymphoma kinase (ALK)‐positive lung cancer has been rapidly evolving since the introduction of several ALK tyrosine kinase inhibitors (ALK‐TKI) in clinical practice. However, the acquired resistance to these drugs has become an important issue. In this study, we collected a total of 112 serial biopsy samples from 32 patients with ALK‐positive lung cancer during multiple ALK‐TKI treatments to reveal the resistance mechanisms to ALK‐TKI. Among 32 patients, 24 patients received more than two ALK‐TKI. Secondary mutations were observed in 8 of 12 specimens after crizotinib failure (G1202R, G1269A, I1171T, L1196M, C1156Y and F1245V). After alectinib failure, G1202R and I1171N mutations were detected in 7 of 15 specimens. G1202R, F1174V and G1202R, and P‐gp overexpression were observed in 3 of 7 samples after ceritinib treatment. L1196M + G1202R, a compound mutation, was detected in 1 specimen after lorlatinib treatment. ALK‐TKI treatment duration was longer in the on‐target treatment group than that in the off‐target group (13.0 vs 1.2 months). In conclusion, resistance to ALK‐TKI based on secondary mutation in this study was similar to that in previous reports, except for crizotinib resistance. Understanding the appropriate treatment matching resistance mechanisms contributes to the efficacy of multiple ALK‐TKI treatment strategies.

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Section: Methodsmentioning

confidence: 99%

Drug resistance mechanisms in Japanese anaplastic lymphoma kinase‐positive non–small cell lung cancer and the clinical responses based on the resistant mechanisms

et al. 2020

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“…PD-L1 interacts with the receptor, programmed cell death 1 (PD-1), on activated cytotoxic T cells through the IgV domain. Next, PD-1 forms aggregates with TCR and costimulatory receptor CD28 and recruits the SHP2 phosphatase, leading to its dephosphorylation and inactivation (165,166). Last, effector T cells become exhausted by the decreased phosphorylation of crucial signaling molecules which regulate activation and proliferation mediated by NFAT (165)(166)(167).…”

Section: Impaired Dcs Recruitment: Ccl4 Inhibitionmentioning

confidence: 99%

WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

et al. 2019

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WNT/β-catenin signaling is involved in many physiological processes. Its implication in embryonic development, cell migration, and polarization has been shown. Nevertheless, alterations in this signaling have also been related with pathological events such as sustaining and proliferating the cancer stem cell (CSC) subset present in the tumor bulk. Related with this, WNT signaling has been associated with the maintenance, expansion, and epithelial-mesenchymal transition of stem cells, and furthermore with two distinctive features of this tumor population: therapeutic resistance (MDR, multidrug resistance) and immune escape. These mechanisms are developed and maintained by WNT activation through the transcriptional control of the genes involved in such processes. This review focuses on the description of the best known WNT pathways and the molecules involved in them. Special attention is given to the WNT cascade proteins deregulated in tumors, which have a decisive role in tumor survival. Some of these proteins function as extrusion pumps that, in the course of chemotherapy, expel the drugs from the cells; others help the tumoral cells hide from the immune effector mechanisms. Among the WNT targets involved in drug resistance, the drug extrusion pump MDR-1 (P-GP, ABCB1) and the cell adhesion molecules from the CD44 family are highlighted. The chemokine CCL4 and the immune checkpoint proteins CD47 and PD-L1 are included in the list of WNT target molecules with a role in immunity escape. This pathway should be a main target in cancer therapy as WNT signaling activation is essential for tumor progression and survival, even in the presence of the anti-tumoral immune response and/or antineoplastic drugs. The appropriate design and combination of anti-tumoral strategies, based on the modulation of WNT mediators and/or protein targets, could negatively affect the growth of tumoral cells, improving the efficacy of these types of therapies.

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“…Recently, drug resistance phenomenon has also been observed in immunotherapy for tumours treatment. For example, PD-1 blockade therapy has been found to promote the expression of pro-tumour inammatory cytokines that potentially counteract the anti-tumour effects of PD-1 blockade, 92,93 and the anti-PD-L1 antibody "decoys" mechanism disables the anti-PD-L1 antibody blockade therapy; 16 Most astonishingly, when the chimeric antigen receptors (CARs) T cells were used for tumour treatment, CARs could provoke reversible antigen loss via trogocytosis, and the target antigen could be transferred to T cells through this active process, thereby reducing target antigen density on tumour cells and inhibiting T cell activity by initiating fratricide T cell killing and promoting T cell exhaustion. 94 Based on these understandings, we speculate that the future direction might lie in the combined therapy based on PD-1/PD-L1 blockade and personalized tumour vaccines.…”

Section: Conclusion and Prospectsmentioning

confidence: 99%

“…In addition to abovementioned, recent studies discovered that some tumour cells could secrete a large proportion of their PD-L1 on exosomes instead of presenting the PD-L1 on their cell surface. Exosomal PD-L1 transmit immunosuppressive signals to draining lymph node to suppresses T cell function and inactivate immune cells at its source, 15 and some tumour cells even secret a PD-L1 splicing variants, working as "decoys" of PD-L1 antibody, to induce the tumour resistance to PD-L1 blockade, 16 which may also be responsible for the failures of PD-1/PD-L1 blockade therapy.…”

Section: Introductionmentioning

confidence: 99%