Single-cell expression profiles of melanoma Tumors harbor multiple cell types that are thought to play a role in the development of resistance to drug treatments. Tirosh et al. used single-cell sequencing to investigate the distribution of these differing genetic profiles within melanomas. Many cells harbored heterogeneous genetic programs that reflected two different states of genetic expression, one of which was linked to resistance development. Following drug treatment, the resistance-linked expression state was found at a much higher level. Furthermore, the environment of the melanoma cells affected their gene expression programs. Science, this issue p. 189 Melanoma cells show transcriptional heterogeneity. To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context, and a drug-resistance program. In particular, all tumors harbored malignant cells from two distinct transcriptional cell states, such that tumors characterized by high levels of the MITF transcription factor also contained cells with low MITF and elevated levels of the AXL kinase. Single-cell analyses suggested distinct tumor microenvironmental patterns, including cell-to-cell interactions. Analysis of tumor-infiltrating T cells revealed exhaustion programs, their connection to T cell activation and clonal expansion, and their variability across patients. Overall, we begin to unravel the cellular ecosystem of tumors and how single-cell genomics offers insights with implications for both targeted and immune therapies.

Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq

Immunotherapy has revolutionized cancer treatment and rejuvenated the field of tumor immunology Several types of immunotherapy, including adoptive cell transfer (ACT) and immune checkpoint inhibitors (ICIs), have obtained durable clinical responses, but their efficacies vary, and only subsets of cancer patients can benefit from them Immune infiltrates in the tumor microenvironment (TME) have been shown to play a key role in tumor development and will affect the clinical outcomes of cancer patients Comprehensive profiling of tumor-infiltrating immune cells would shed light on the mechanisms of cancer–immune evasion, thus providing opportunities for the development of novel therapeutic strategies However, the highly heterogeneous and dynamic nature of the TME impedes the precise dissection of intratumoral immune cells With recent advances in single-cell technologies such as single-cell RNA sequencing (scRNA-seq) and mass cytometry, systematic interrogation of the TME is feasible and will provide insights into the functional diversities of tumor-infiltrating immune cells In this review, we outline the recent progress in cancer immunotherapy, particularly by focusing on landmark studies and the recent single-cell characterization of tumor-associated immune cells, and we summarize the phenotypic diversities of intratumoral immune cells and their connections with cancer immunotherapy We believe such a review could strengthen our understanding of the progress in cancer immunotherapy, facilitate the elucidation of immune cell modulation in tumor progression, and thus guide the development of novel immunotherapies for cancer treatment

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The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications.

Single-Cell Analyses Inform Mechanisms of Myeloid-Targeted Therapies in Colon Cancer.

Cell-cell interactions orchestrate organismal development, homeostasis and single-cell functions. When cells do not properly interact or improperly decode molecular messages, disease ensues. Thus, the identification and quantification of intercellular signalling pathways has become a common analysis performed across diverse disciplines. The expansion of protein-protein interaction databases and recent advances in RNA sequencing technologies have enabled routine analyses of intercellular signalling from gene expression measurements of bulk and single-cell data sets. In particular, ligand-receptor pairs can be used to infer intercellular communication from the coordinated expression of their cognate genes. In this Review, we highlight discoveries enabled by analyses of cell-cell interactions from transcriptomic data and review the methods and tools used in this context.

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Deciphering cell-cell interactions and communication from gene expression.

A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells.

Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma.

Background HER2-targeted therapy provides survival benefits to HER2-mutant non-small cell lung cancer (NSCLC). A better understanding of the clinical and genomic characterization of treatment-naïve HER2-positive NSCLC, as well as the efficacy of and resistance to HER2-targeted therapy in HER2-altered NSCLC, could promote further improvement of HER2 targeted therapy. Methods HER2-altered NSCLC patients was retrospectively included and their genomic profiles were performed by next-generation sequencing. The clinical outcomes included overall response rate, disease control rate and progression-free survival. Results Among 176 treatment-naïve patients with HER2 alterations, 64.8% harbored HER2 mutations with/without HER2 amplification, and 35.2% carried HER2 amplification only. Molecular characterization was correlated with tumor stage that late-stage NSCLC with HER2 oncogenic mutations showed a higher prevalence of TP53 mutations and a higher tumor mutation burden. However, this correlation was not found in patients with HER2 amplification only. Twenty-one patients with HER2 alterations treated with pyrotinib or afatinib were retrospectively enrolled. Pyrotinib yielded a longer median progression-free survival than afatinib (5.9 [95% CI, 3.8-13.0] vs. 4.0 months [95% CI, 1.9-6.3], P = 0.06) in these patients. Analysis of the genomic profiles before and after anti-HER2 targeted therapies identified de novo HER2 copy number gain and G518W mutation, as well as mutations involving DNA damage repair signaling, SWI–SNF complex, and epigenetic regulations as potential resistance mechanisms. Conclusion HER2-mutant NSCLC had different molecular features from HER2-amplified NSCLC, and its genomic profile was dependent of tumor stage. Pyrotinib had superior therapeutic effects than afatinib in HER2-altered NSCLC, although larger cohorts are warranted to validate it. HER2-dependent and -independent resistance mechanisms to afatinib and pyrotinib were unveiled.

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Yanjie Han

Papers

Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma.

Genomic landscape and efficacy of HER2-targeted therapy in patients with HER2-mutant non-small cell lung cancer