The frequency and inter-relationship of PD-L1 expression and tumour mutational burden across multiple types of advanced solid tumours in China

Chen, Yanhui; Wang, Yating; Luo, Hongli; Meng, Xue; Zhu, Wei; Wang, Di; Zeng, Hui; Zhang, Henghui

doi:10.1186/s40164-020-00173-3

Cited by 28 publications

(23 citation statements)

References 57 publications

(52 reference statements)

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“…Detailed classification of tumor-infiltrating lymphocytes (TILs) and identification of cellular crosstalk in AML BM niche will provide important means of assistance based on existed mature chemotherapies [ 90 ]. By examining immune cell types can help to formulate personalized high-efficiency immunotherapy trials.…”

Section: Resultsmentioning

confidence: 99%

Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment

et al. 2021

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Background Knowledge of immune cell phenotypes, function, and developmental trajectory in acute myeloid leukemia (AML) microenvironment is essential for understanding mechanisms of evading immune surveillance and immunotherapy response of targeting special microenvironment components. Methods Using a single-cell RNA sequencing (scRNA-seq) dataset, we analyzed the immune cell phenotypes, function, and developmental trajectory of bone marrow (BM) samples from 16 AML patients and 4 healthy donors, but not AML blasts. Results We observed a significant difference between normal and AML BM immune cells. Here, we defined the diversity of dendritic cells (DC) and macrophages in different AML patients. We also identified several unique immune cell types including T helper cell 17 (TH17)-like intermediate population, cytotoxic CD4+ T subset, T cell: erythrocyte complexes, activated regulatory T cells (Treg), and CD8+ memory-like subset. Emerging AML cells remodels the BM immune microenvironment powerfully, leads to immunosuppression by accumulating exhausted/dysfunctional immune effectors, expending immune-activated types, and promoting the formation of suppressive subsets. Conclusion Our results provide a comprehensive AML BM immune cell census, which can help to select pinpoint targeted drug and predict efficacy of immunotherapy.

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Section: Resultsmentioning

confidence: 99%

Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment

et al. 2021

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“…It was reported that a high density of CD8+ cells was associated with a higher median OS time in 163 NSCLC patients who received durvalumab (P<0.01) (32). Some studies have also found that high infiltration of CD8+ T cells is correlated with a relatively good response in patients treated with ICIs (12,(19)(20)(21). A previous study found that the level of CD8+ T cells was significantly higher in patients achieving CR/PR than in those with SD/PD in melanoma (P < 0.0001) (32).…”

Section: Discussionmentioning

confidence: 98%

“…In addition to TMB and PD-L1, multiple immune cell subsets have been assessed to determine their predictive value for immunotherapy outcomes in NSCLC (12,13,18). It was reported that the infiltration of CD8+ T cells was associated with ICI efficacy (12,(19)(20)(21). Tumor-associated macrophages (TAMs) are important immune cells in the tumor microenvironment (TME), as they mediate tumor progression by regulating TME (22).…”

Section: Introductionmentioning

confidence: 99%

Low Infiltration of CD8+ PD-L1+ T Cells and M2 Macrophages Predicts Improved Clinical Outcomes After Immune Checkpoint Inhibitor Therapy in Non-Small Cell Lung Carcinoma

Liu

et al. 2021

Front. Oncol.

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BackgroundMany clinical studies have shown that patients with non-small cell lung carcinoma (NSCLC) can benefit from immune checkpoint inhibitor (ICI) therapy; however, PD-L1 and tumor mutation burden (TMB), which are recommended by the NCCN guidelines, are still insufficient in predicting the response to and prognosis of immunotherapy. Given the widespread use of ICIs, it is important to find biomarkers that can predict immunotherapy outcomes in NSCLC patients, and the exploration of additional effective biomarkers for ICI therapy is urgently needed.MethodsA total of 33 stage II-IV NSCLC patients were included in this study. We analyzed immune markers in biopsy and surgical tissue resected from these patients before treatment with ICIs. We examined the infiltration of immune cells and expression of PD-L1 in immune cells using fluorescent multiplex immunohistochemistry (mIHC) stained with CD8/CD68/CD163/PD-L1 antibodies.ResultsIn this cohort, we observed that the levels of CD8+ T cells, CD8+PD-L1+ T cells, and CD68+CD163+ M2 macrophages in the total region were independent prognostic factors for progression-free survival (PFS) in NSCLC patients treated with ICIs (HR=0.04, P=0.013; HR=17.70, P=0.026; and HR=17.88, P=0.011, respectively). High infiltration of CD8+ T cells and low infiltration of CD8+PD-L1+ T cells throughout the region were correlated with prolonged PFS (P=0.016 and P=0.02, respectively). No statistically significant difference was observed for CD68+CD163+ M2 macrophages. The joint parameters CD8+ high/CD8+PD-L1+ low, CD8+ high/CD68+CD163+ low and CD8+PD-L1+ low/CD68+CD163+ low predicted better PFS than other joint parameters (P<0.01, P<0.01, and P<0.001, respectively), and they also demonstrated stronger stratification than single biomarkers. The response rate of patients with high infiltration of CD8+ T cells was significantly higher than that of those with low infiltration (P<0.01), and the joint parameters CD8+/CD8+PD-L1+ and CD8+/CD68+CD163+ also demonstrated stronger stratification than single biomarkers.ConclusionsThis retrospective study identified the predictive value of CD8+PD-L1+ T cells, CD8+ T cells, and CD68+CD163+ M2 macrophages in NSCLC patients who received ICIs. Interestingly, our results indicate that the evaluation of joint parameters has certain significance in guiding ICI treatment in NSCLC patients.

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“…Actually, for these non-responders undergoing treatment, the PD-1-PD-L1 axis is not the sole speed-limiting step in the Cancer-Immunity Cycle [ 20 ]. A group of factors including other immune checkpoints [ 21 – 23 ], cancer neoantigens [ 24 – 26 ], gut microbiota [ 27 , 28 ], soluble MHC related molecules [ 29 ], and cytokines in the tumor microenvironment (TME) also affect anti-cancer immune response [ 30 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

The construction, expression, and enhanced anti-tumor activity of YM101: a bispecific antibody simultaneously targeting TGF-β and PD-L1

Yi¹,

Zhang²,

Li³

et al. 2021

J Hematol Oncol

138

124

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Background Therapeutic antibodies targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis induce potent and durable anti-tumor responses in multiple types of cancers. However, only a subset of patients benefits from anti-PD-1/PD-L1 therapies. As a negative regulator of anti-tumor immunity, TGF-β impairs the efficacy of anti-PD-1/PD-L1 and induces drug resistance. Developing a novel treatment strategy to simultaneously block PD-1/PD-L1 and TGF-β would be valuable to enhance the effect of anti-PD-1/PD-L1 and relieve drug resistance. Methods Based on the Check-BODY™ technology platform, we developed an anti-TGF-β/PD-L1 bispecific antibody YM101. The bioactivity of the anti-TGF-β moiety was determined by Smad-luciferase reporter assay, transwell assay, western blotting, CCK-8, and flow cytometry. The bioactivity of the anti-PD-L1 moiety was measured by T cell activation assays. EMT-6, CT26, and 3LL tumor models were used to investigate the anti-tumor activity of YM101 in vivo. RNA-seq, immunohistochemical staining, and flow cytometry were utilized to analyze the effect of YM101 on the tumor microenvironment. Results YM101 could bind to TGF-β and PD-L1 specifically. In vitro experiments showed that YM101 effectively counteracted the biological effects of TGF-β and PD-1/PD-L1 pathway, including activating Smad signaling, inducing epithelial-mesenchymal transition, and immunosuppression. Besides, in vivo experiments indicated the anti-tumor activity of YM101 was superior to anti-TGF-β and anti-PD-L1 monotherapies. Mechanistically, YM101 promoted the formation of ‘hot tumor’: increasing the numbers of tumor infiltrating lymphocytes and dendritic cells, elevating the ratio of M1/M2, and enhancing cytokine production in T cells. This normalized tumor immune microenvironment and enhanced anti-tumor immune response might contribute to the robust anti-tumor effect of YM101. Conclusion Our results demonstrated that YM101 could simultaneously block TGF-β and PD-L1 pathways and had a superior anti-tumor effect compared to the monotherapies.

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The frequency and inter-relationship of PD-L1 expression and tumour mutational burden across multiple types of advanced solid tumours in China

Cited by 28 publications

References 57 publications

Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment

Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment

Low Infiltration of CD8+ PD-L1+ T Cells and M2 Macrophages Predicts Improved Clinical Outcomes After Immune Checkpoint Inhibitor Therapy in Non-Small Cell Lung Carcinoma

The construction, expression, and enhanced anti-tumor activity of YM101: a bispecific antibody simultaneously targeting TGF-β and PD-L1

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