Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer

Zhang, Yuanyuan; Chen, Hongyan; Mo, Hongnan; Hu, Xueda; Gao, Ranran; Zhao, Yahui; Liu, Baolin; Niu, Lijuan; Sun, Xiaoying; Yu, Xiao; Wang, Yong; Chang, Qing; Gong, Tongyang; Guan, Xiuwen; Hu, Ting; Qian, Tianyi; Xu, Binghe; Ma, Fei; Zhang, Zemin; Liu, Zhihua

doi:10.1016/j.ccell.2021.09.010

Cited by 412 publications

(459 citation statements)

References 78 publications

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“…In patients responsive to drug combination, an increase of lymphoid tissue inducer cells, follicular B cells, CXCL13+ T cells, and type 1 dendritic cells was detected. The latter decreased after paclitaxel monotherapy [90]. These data suggest the role of CXCL13+ T cells in the responses to anti-PD-L1 therapies.…”

Section: Recent Results On Precision Medicine Applied To Colorectal Carcinomamentioning

confidence: 67%

A Portrait of Intratumoral Genomic and Transcriptomic Heterogeneity at Single-Cell Level in Colorectal Cancer

et al. 2021

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In the study of cancer, omics technologies are supporting the transition from traditional clinical approaches to precision medicine. Intra-tumoral heterogeneity (ITH) is detectable within a single tumor in which cancer cell subpopulations with different genome features coexist in a patient in different tumor areas or may evolve/differ over time. Colorectal carcinoma (CRC) is characterized by heterogeneous features involving genomic, epigenomic, and transcriptomic alterations. The study of ITH is a promising new frontier to lay the foundation towards successful CRC diagnosis and treatment. Genome and transcriptome sequencing together with editing technologies are revolutionizing biomedical research, representing the most promising tools for overcoming unmet clinical and research challenges. Rapid advances in both bulk and single-cell next-generation sequencing (NGS) are identifying primary and metastatic intratumoral genomic and transcriptional heterogeneity. They provide critical insight in the origin and spatiotemporal evolution of genomic clones responsible for early and late therapeutic resistance and relapse. Single-cell technologies can be used to define subpopulations within a known cell type by searching for differential gene expression within the cell population of interest and/or effectively isolating signal from rare cell populations that would not be detectable by other methods. Each single-cell sequencing analysis is driven by clustering of cells based on their differentially expressed genes. Genes that drive clustering can be used as unique markers for a specific cell population. In this review we analyzed, starting from published data, the possible achievement of a transition from clinical CRC research to precision medicine with an emphasis on new single-cell based techniques; at the same time, we focused on all approaches and issues related to this promising technology. This transition might enable noninvasive screening for early diagnosis, individualized prediction of therapeutic response, and discovery of additional novel drug targets.

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Section: Recent Results On Precision Medicine Applied To Colorectal Carcinomamentioning

confidence: 67%

A Portrait of Intratumoral Genomic and Transcriptomic Heterogeneity at Single-Cell Level in Colorectal Cancer

et al. 2021

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“…Instead, cells belonging to cluster 5, highly expressed gene markers associated with proliferation such as Ccnb2, Mki67 and Top2a genes defining this cluster as M2-like proliferative. While cluster 2 highly expressed C1qa/C1qc genes that were found upregulated in a previously reported M2-like tumor associated macrophage cluster 47 . On the other hand, cluster 1 resulted in being associated with a M1-like macrophagic population due to the expression of Ly6c1/Ly6c2 gene 56,58 .…”

Section: M1-and M2 -Like Tumor Associated Macrophages Populations In the Emt6 Tmesmentioning

confidence: 61%

“…Although recently, many studies focused on the immune TME of BC 47,60,63,64 , specific knowledge about their immune cell composition is still limited. Here we report a fine characterization of the immune transcriptional profiles of almost 50,000 single cells in two TNBC murine cell line TMEs.…”

Section: Discussionmentioning

confidence: 99%

“…Also depending on the results and the expression of known gene markers the granularity was chosen accordingly (0.2 and 0.3 for Cd4 and Cd8 respectively in 4T1 cell line, 0.1 and 0.2 for B in the 4T1 and EMT6 cell line respectively, 0.4 for macrophages in EMT6 cell line). The sub-clusters cell assignment was performed only with manual curation by choosing a known set of genes from relevant studies that focus on the same cell populations [44][45][46][47] in similar mouse models and evaluating their expression in the sub-clusters.…”

Section: Sub-clusteringmentioning

confidence: 99%

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A single-cell transcriptomic landscape of innate and adaptive intratumoral immunity in triple negative breast cancer during chemo- and immunotherapies

Carpen

Falvo

Orecchioni

et al. 2021

Preprint

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Breast cancer (BC) constitutes a major health problem worldwide, making it the most common malignancy in women. Current treatment options for BC depend primarily on histological type, molecular markers, clinical aggressiveness and stage of disease. Immunotherapy, such as anti-PD-1, have shown combinatorial clinical activity with chemotherapy in triple negative breast cancer (TNBC) delineating some therapeutic combinations as more effective than others. However, a clear overview of the main immune cell populations involved in these treatments has never been provided.Here, an assessment of the immune landscape in the tumour microenvironment (TME) of two TNBC mouse models (4T1 and EMT6 cell lines) has been performed using single-cell RNA sequencing (scRNA-seq) technology. Specifically, immune cells were evaluated in untreated conditions and after being treated with chemotherapy or immunotherapy used as single agents or in combination. A decrease of regulatory T cells, compared to the untreated TME, was found in treatments with in vivo efficacy as well as γδ T cells, which have a pro-tumoral activity in mice. Focusing on Cd8 T cells, across all the conditions, a general increase of exhausted-like Cd8 T cells was confirmed in pre-clinical treatments with low efficacy; on the other hand, an opposite trend was found for the proliferative Cd8 T cells. Regarding macrophages, M2-like cells were found enriched in treatments with low efficacy while opposite behaviour was associated with M1-like macrophages. For both cell lines, similar proportions of B cells were detected with an increase of proliferative B cells in treatments that involved cisplatin in combination with anti-PD-1. The fine-scale characterization of the immune TME in this work can lead to new insights on the diagnosis and treatment of TNBC for a possible application at the clinical level.

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“…However, it has recently been demonstrated that a high abundance of PD1 high /CXCL13+ CD4+ and CD8+ T cells, as observed in IE1 tumors, is highly predictive for increased T cell expansion upon anti-PD1 treatment across all breast cancer subtypes 15 and positively influences response to anti-PD-L1 treatment in triple-negative breast cancer. 75 Irrespective of prognostic or predictive value, we have shown that IE1 and IE2 represent two distinct immune environments with respect to tumor antigen presentation, T cell phenotypes, cytotoxic potential, and cellular crosstalk, all of which are likely to affect immunotherapy response. PD-L1 is currently the main marker used to stratify patients for immune checkpoint therapy in breast cancer 76 .…”

Section: Discussionmentioning

confidence: 89%

A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer

Tietscher

Wagner²,

Anzeneder³

et al. 2022

Preprint

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Immune checkpoint therapy in breast cancer remains restricted to triple negative patients, and long-term clinical benefit is rare. The primary aim of immune checkpoint blockade is to prevent or reverse exhausted T cell states, but the causes and implications of T cell exhaustion in breast tumors are not well understood. Here, we used single-cell transcriptomics combined with imaging mass cytometry to comprehensively study exhausted and non-exhausted immune environments in human breast tumors, with a focus on Luminal subtypes. We found that the presence of a PD-1high exhaustion-like T cell phenotype was indicative of an inflammatory immune environment with a characteristic cytotoxic profile and spatial features. Accumulation of natural killer T cells and increased myeloid cell activation in exhausted immune environments provide further support for tissue inflammation in these environments. Consistent with this, our comprehensive map of cellular interactions within the breast tumor microenvironment revealed elevated immunomodulatory, chemotactic, and cytokine signaling in exhausted environments. These data reveal fundamental differences between exhausted and non-exhausted immune environments within Luminal breast cancer, and show that expression of PD-1 and CXCL13 on T cells, and MHC-I – but not PD-L1 – on tumor cells are strong distinguishing features between these environments; these factors are potential new biomarkers for patient stratification.

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Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer

Cited by 412 publications

References 78 publications

A Portrait of Intratumoral Genomic and Transcriptomic Heterogeneity at Single-Cell Level in Colorectal Cancer

A Portrait of Intratumoral Genomic and Transcriptomic Heterogeneity at Single-Cell Level in Colorectal Cancer

A single-cell transcriptomic landscape of innate and adaptive intratumoral immunity in triple negative breast cancer during chemo- and immunotherapies

A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer

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