B7-H1 antibodies lose antitumor activity due to activation of p38 MAPK that leads to apoptosis of tumor-reactive CD8+ T cells

Liu, Xin; Wu, Xiaosheng; Cao, Siyu; Harrington, Susan M.; Yin, Peng; Mansfield, Aaron S.; Dong, Haidong

doi:10.1038/srep36722

Cited by 36 publications

(36 citation statements)

References 28 publications

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“…B16F10 (1 × 10 5 cells) mouse melanoma cells were s.c. injected into mice in the right flank, followed with treatment of i.p. injection of anti-PD-1 (clone G4) and PD-L1 antibody (clone 10B5) (52) or control IgG at 100 μg of each starting on day 7 for a total of 5 doses at 3-day intervals. Both G4 and 10B5 antibodies were produced at Mayo Clinic Antibody Core facility.…”

Section: Methodsmentioning

confidence: 99%

CX3CR1 identifies PD-1 therapy–responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy

Yan¹,

Cao²,

Liu³

et al. 2018

JCI Insight

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121

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Although immune checkpoint inhibitors have resulted in durable clinical benefits in a subset of patients with advanced cancer, some patients who did not respond to initial anti-PD-1 therapy have been found to benefit from the addition of salvage chemotherapy. However, the mechanism responsible for the successful chemoimmunotherapy is not completely understood. Here we show that a subset of circulating CD8+ T cells expressing the chemokine receptor CX3CR1 are able to withstand the toxicity of chemotherapy and are increased in patients with metastatic melanoma who responded to chemoimmunotherapy (paclitaxel and carboplatin plus PD-1 blockade). These CX3CR1+CD8+ T cells have effector memory phenotypes and the ability to efflux chemotherapy drugs via the ABCB1 transporter. In line with clinical observation, our preclinical models identified an optimal sequencing of chemoimmunotherapy that resulted in an increase of CX3CR1+CD8+ T cells. Taken together, we found a subset of PD-1 therapy-responsive CD8+ T cells that were capable of withstanding chemotherapy and executing tumor rejection with their unique abilities of drug efflux (ABCB1), cytolytic activity (granzyme B and perforin), and migration to and retention (CX3CR1 and CD11a) at tumor sites. Future strategies to monitor and increase the frequency of CX3CR1+CD8+ T cells may help to design effective chemoimmunotherapy to overcome cancer resistance to immune checkpoint blockade therapy.

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Section: Methodsmentioning

confidence: 99%

CX3CR1 identifies PD-1 therapy–responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy

Yan¹,

Cao²,

Liu³

et al. 2018

JCI Insight

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121

120

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“…Third, T-cell-expressed PD-L1 can function as a receptor in T-cells. This so-called “back-signaling” can promote T-helper 1 (Th1)-to-Th17 switch in CD4 T-cells [ 29 ], a non-responsive (anergic) phenotype in CD8 T-cells [ 29 ] and apoptosis in activated T-cells [ 30 ]; the ligation of PD-L1 on T-cells was as efficient as PD-1 ligation in suppressing T-cell functionality [ 29 ]. In addition to PD-1 and PD-L1, activated T-cells can also express CD80 known to restrain T-cell effector function through CTLA-4 [ 31 ]; the role for PD-L1–CD80 interactions in T-cell bidirectional signaling remains to be addressed.…”

Section: Pd-l1 Expression On Non-tumor Cellsmentioning

confidence: 99%

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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“…In this review, we will consider how PD-L1/PD-1 checkpoint blockade therapies affect the priming phase of antitumor CD8 + T cell responses. Activated CD8 + T cells also express PD-L1, and it has been demonstrated that this expression of PD-L1 plays a role in the survival of activated CD8 + T cells during the contraction phase of an immune response ( 41 , 42 ). Accordingly, the CD8 + T cell intrinsic role for PD-L1/PD-1 signaling will also be examined.…”

Section: Introductionmentioning

confidence: 99%

Functional Expression of Programmed Death-Ligand 1 (B7-H1) by Immune Cells and Tumor Cells

2017

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The programmed death-1 (PD-1) and its ligand PD-L1 (B7-H1) signaling pathway has been the focus of much enthusiasm in the fields of tumor immunology and oncology with recent FDA approval of the anti-PD-1 antibodies pembrolizumab and nivolumab and the anti-PD-L1 antibodies durvalumab, atezolimuab, and avelumab. These therapies, referred to here as PD-L1/PD-1 checkpoint blockade therapies, are designed to block the interaction between PD-L1, expressed by tumor cells, and PD-1, expressed by tumor-infiltrating CD8+ T cells, leading to enhanced antitumor CD8+ T cell responses and tumor regression. The influence of PD-L1 expressed by tumor cells on antitumor CD8+ T cell responses is well characterized, but the impact of PD-L1 expressed by immune cells has not been well defined for antitumor CD8+ T cell responses. Although PD-L1 expression by tumor cells has been used as a biomarker in selection of patients for PD-L1/PD-1 checkpoint blockade therapies, patients whose tumor cells lack PD-L1 expression often respond positively to PD-L1/PD-1 checkpoint blockade therapies. This suggests that PD-L1 expressed by non-malignant cells may also contribute to antitumor immunity. Here, we review the functions of PD-L1 expressed by immune cells in the context of CD8+ T cell priming, contraction, and differentiation into memory populations, as well as the role of PD-L1 expressed by tumor cells in regulating antitumor CD8+ T cell responses.

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B7-H1 antibodies lose antitumor activity due to activation of p38 MAPK that leads to apoptosis of tumor-reactive CD8+ T cells

Cited by 36 publications

References 28 publications

CX3CR1 identifies PD-1 therapy–responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy

CX3CR1 identifies PD-1 therapy–responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy

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

Functional Expression of Programmed Death-Ligand 1 (B7-H1) by Immune Cells and Tumor Cells

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