Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy

Mayoux, Maud; Roller, Andreas; Pulko, Vesna; Sammicheli, Stefano; Chen, Stanford; Sum, Eva; Jöst, Christian; Fransen, Marieke F.; Buser, Regula B.; Kowanetz, Marcin; Rommel, Karolin; Matos, Inês; Colombetti, Sara; Belousov, Anton; Karanikas, Vaios; Ossendorp, Ferry; Hegde, Priti S.; Chen, Daniel S.; Umaña, Pablo; Perro, Mario; Klein, Christian; Xu, Wei

doi:10.1126/scitranslmed.aav7431

Cited by 270 publications

(224 citation statements)

References 29 publications

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“…Thus, we can speculate that the addition of anti-PDL2 Ab to anti-PDL1 therapy soon after immunogenic chemotherapy maximizes the ability of CD103 + DCs to cross-present tumor antigens by shielding two non-redundant immunoinhibitory signals, ultimately leading to an efficient and long-lasting CD8 + T cell stimulation. Along these lines, Mayoux and colleagues have recently shown that blocking PDL1 on DCs allow a better stimulation of T cell priming with positive immunological and likely clinical consequences for checkpoint blockade therapy in cancer patients [43]. In addition to CD103 + DCs, intratumoral recruitment of eosinophils may contribute to tumor rejection through both direct cytotoxicity towards tumor cells and by secreting chemokines capable of attracting CD8 + T cells as recently reported [20,44,45].…”

Section: Discussionmentioning

confidence: 93%

Tumor-Intrinsic or Drug-Induced Immunogenicity Dictates the Therapeutic Success of the PD1/PDL Axis Blockade

Rossi

Lucarini

Macchia

et al. 2020

Cells

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Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment providing unprecedented clinical benefits. However, many patients do not respond to ICIs as monotherapy or develop resistance. Combining ICI-based immunotherapy with chemotherapy is a promising strategy to increase response rates, but few rationale-driven chemo-immunotherapy combinations have reached the clinical arena thus far. In the present study, we show that combined anti-PDL1 and anti-PDL2 antibodies optimally synergize with cyclophosphamide but not with cisplatin, and that the magnitude and duration of the therapeutic response is dependent on the immunogenic potential of the drug and of the tumor itself. Hallmarks of successful therapeutic outcomes were the enhanced infiltration by myeloid (mainly cross-presenting dendritic cells, eosinophils, and monocytic myeloid cells) and T lymphocytes into the tumor tissue and the expansion of circulating memory pools. Overall, our results suggest that immunomodulating chemotherapy can be exploited to increase the efficacy of PD1/PDL axis inhibitors in vivo, and that the magnitude of the synergic therapeutic response is affected by tumor-intrinsic immunogenicity.

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Section: Discussionmentioning

confidence: 93%

Tumor-Intrinsic or Drug-Induced Immunogenicity Dictates the Therapeutic Success of the PD1/PDL Axis Blockade

Rossi

Lucarini

Macchia

et al. 2020

Cells

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“…Within the solid tumor microenvironment, PD-L1 can be expressed on many cells of hematopoietic origin, often collectively referred to as “immune infiltrate”, including dendritic cells [ 17 ], tumor-associated macrophages (TAMs) [ 4 , 18 ], myeloid-derived suppressor cells (MDSCs) [ 19 ] and T-cells [ 3 ]. PD-L1 can also be expressed on the non-hematopoietic stromal elements, principally the endothelial cells of the tumor vasculature [ 20 ] and cancer-associated fibroblasts [ 21 ].…”

Section: Pd-l1 Expression On Non-tumor Cellsmentioning

confidence: 99%

“…PD-L1 expressed on DCs provides a direct T-cell inhibitory input via PD-1 but also helps override T-cell activation in the context of antigen recognition [ 17 , 25 ]. PD-L1 has two binding partners, the inhibitory receptor PD-1 on T-cells and the co-stimulatory molecule CD80 (B7.1) on antigen-presenting cells.…”

Section: Pd-l1 Expression On Non-tumor Cellsmentioning

confidence: 99%

“…During the DC-T-cell cross-talk, PD-L1 on the DC binds to and sequesters CD80 in cis , while the excess of unbound PD-L1 interacts with PD-1 on the T-cell, resulting in functional inactivation. Anti-PD-L1 antibodies release CD80 from this sequestered form and re-instate the CD80-CD28 co-stimulatory interaction while simultaneously blocking the PD-L1-PD-1 inhibitory pathway, resulting in augmented T-cell activation upon antigen recognition [ 17 ] ( Figure 2 ). Of note, the inability of PD-L1 to bind CD80 in cis resulted in attenuated immune responses, including anti-tumor responses [ 25 ].…”

Section: Pd-l1 Expression On Non-tumor Cellsmentioning

confidence: 99%

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Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy

Shklovskaya

Rizos

2020

IJMS

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Immunotherapies blocking immune inhibitory receptors programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) on T-cells have dramatically improved patient outcomes in a range of advanced cancers. However, the lack of response, and the development of resistance remain major obstacles to long-term improvements in patient outcomes. There is significant interest in the clinical use of biomarkers to improve patient selection, and the expression of PD-1 ligand 1 (PD-L1) is often reported as a potential biomarker of response. However, accumulating evidence suggests that the predictive value of PD-L1 expression in tumor biopsies is relatively low due, in part, to its complex biology. In this review, we discuss the biological consequences of PD-L1 expression by various cell types within the tumor microenvironment, and the complex mechanisms that regulate PD-L1 expression at the genomic, transcriptomic and proteomic levels.

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“…Besides tumor cells, PD-L1 is also expressed in various types of cells, including activated T cells, NK cells, dendritic cells (DC) and myeloid-derived suppressor cells (MDSCs) [49,[51][52][53][54]. In this study, we preliminarily veri ed the feasibility and e cacy of CAR-T cells targeting PD-L1 for the treatment of solid tumors, and we found that PD-L1 was up-regulated in T cells that were activated through either endogenous TCR or CAR signaling, making these activated T cells be the target of anti-PD-L1 T cells.…”

Section: Discussionmentioning

confidence: 99%

Chimeric antigen receptor T cells targeting PD-L1 suppress tumor growth

Qin

Zhao

Chen

et al. 2020

Preprint

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Background: Chimeric antigen receptor T cells (CAR-T cells) therapy has been well recognized for treating B cell-derived malignancy. However, the efficacy of CAR-T cells against solid tumors remains dissatisfactory, partially due to the heterogeneity of solid tumors and T cell exhaustion in tumor microenvironment. PD-L1 is up-regulated in multiple solid tumors, resulting in T cell exhaustion upon binding to its receptor PD-1. Methods: Here, we designed a dominant-negative form of PD-1 , dPD1z, a vector containing the extracellular and transmembrane regions of human PD-1, and a CAR vector against PD-L1, CARPD-L1z, a vector employs a high-affinity single-chain variable fragment (scFv) against human PD-L1. These two vectors shared the same intracellular structure, including 4-1BB and TLR2 co-stimulatory domains, and the CD3ζ signaling domain. Results: dPD1z T and CARPD-L1z T cells efficiently lysed PD-L1 + tumor cells and had enhanced cytokine secretion in vitro and suppressed the growth of non-small cell lung cancer (NSCLC), gastric cancer and hepatoma carcinoma in patient-derived xenograft (PDX). However, the combination of anti-mesothelin CAR-T cells (CARMSLNz T) with dPD1z T or CARPD-L1z T cells did not repress tumor growth synergistically in PDX, as CARMSLNz T cells upregulated PD-L1 expression upon activation and were subsequently attacked by dPD1z T or CARPD-L1z T cells. Conclusions: In conclusion, we demonstrate CAR-T cells targeting PD-L1 were effective for suppressing the growth of multiple types of solid tumors in PDX models though their safety needs to be carefully examined.

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Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy

Cited by 270 publications

References 29 publications

Tumor-Intrinsic or Drug-Induced Immunogenicity Dictates the Therapeutic Success of the PD1/PDL Axis Blockade

Tumor-Intrinsic or Drug-Induced Immunogenicity Dictates the Therapeutic Success of the PD1/PDL Axis Blockade

Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy

Chimeric antigen receptor T cells targeting PD-L1 suppress tumor growth

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