ABSTRACT
To better understand intrinsic resistance to immune checkpoint blockade (ICB), we established a comprehensive view of the cellular architecture of the treatment-naive melanoma ecosystem and studied its evolution under ICB. Using single-cell, spatial multi-omics, we showed that the tumor microenvironment promotes the emergence of a complex melanoma transcriptomic landscape. Melanoma cells harboring a mesenchymal-like (MES) state, a population known to confer resistance to targeted therapy, were significantly enriched in early on-treatment biopsies from non-responders to ICB. TCF4 serves as the hub of this landscape by being a master regulator of the MES signature and a suppressor of the melanocytic and antigen presentation transcriptional programs. Targeting TCF4 genetically or pharmacologically, using a bromodomain inhibitor, increased immunogenicity and sensitivity of MES cells to ICB and targeted therapy. We thereby uncovered a TCF4-dependent regulatory network that orchestrates multiple transcriptional programs and contributes to resistance to both targeted therapy and ICB in melanoma.
Subject(s)
Melanoma , Humans , Gene Regulatory Networks , Immunotherapy , Melanocytes , Melanoma/drug therapy , Melanoma/genetics , Transcription Factor 4/genetics , Tumor MicroenvironmentSubject(s)
Graft Rejection , Kidney Transplantation , Humans , Graft Rejection/immunology , Clinical RelevanceABSTRACT
Immune checkpoint therapies have significantly advanced cancer treatment. Nevertheless, the high costs and potential adverse effects associated with these therapies highlight the need for better predictive biomarkers to identify patients who are most likely to benefit from treatment. Unfortunately, the existing biomarkers are insufficient to identify such patients. New high-dimensional spatial technologies have emerged as a valuable tool for discovering novel biomarkers by analysing multiple protein markers at a single-cell resolution in tissue samples. These technologies provide a more comprehensive map of tissue composition, cell functionality, and interactions between different cell types in the tumour microenvironment. In this review, we provide an overview of how spatial protein-based multiplexing technologies have fuelled biomarker discovery and advanced the field of immunotherapy. In particular, we will focus on how these technologies contributed to (i) characterise the tumour microenvironment, (ii) understand the role of tumour heterogeneity, (iii) study the interplay of the immune microenvironment and tumour progression, (iv) discover biomarkers for immune checkpoint therapies (v) suggest novel therapeutic strategies.
Subject(s)
Neoplasms , Tumor Microenvironment , Humans , Neoplasms/drug therapy , Biomarkers , Immunotherapy/methods , Antibodies, Monoclonal/therapeutic use , Biomarkers, Tumor/metabolismABSTRACT
Increasing demand for long-term care facilities (LTCFs) and increasingly complex medical needs of LTCF residents necessitate recruiting new physician graduates and developing programs which provide them with experience and specific skills in geriatric and palliative medicine. We developed an educational program for physicians in training, which combines 1 year of immersion at 20% full-time equivalent with (1) theoretical teaching, (2) clinical exposure under the supervision of a senior LTCF physician, and (3) structured case presentations and debriefing with experienced geriatricians. This article presents a preliminary qualitative evaluation of this program from the perspectives of the trainees, supervising physicians, and public health stakeholders. The program was well accepted by all parties and showed positive effects on trainees' interest in long-term care medicine. Suggestions for improving future programs and their implementation are provided.
Subject(s)
Internship and Residency , Physicians , Humans , Aged , Long-Term Care , Switzerland , Health Facilities , Skilled Nursing FacilitiesABSTRACT
Lymphatic endothelial cells (LECs) of the lymph node (LN) parenchyma orchestrate leukocyte trafficking and peripheral T cell dynamics. T cell responses to immunotherapy largely rely on peripheral T cell recruitment in tumors. Yet, a systematic and molecular understanding of how LECs within the LNs control T cell dynamics under steady-state and tumor-bearing conditions is lacking. Intravital imaging combined with immune phenotyping shows that LEC-specific deletion of the essential autophagy gene Atg5 alters intranodal positioning of lymphocytes and accrues their persistence in the LNs by increasing the availability of the main egress signal sphingosine-1-phosphate. Single-cell RNA sequencing of tumor-draining LNs shows that loss of ATG5 remodels niche-specific LEC phenotypes involved in molecular pathways regulating lymphocyte trafficking and LEC-T cell interactions. Functionally, loss of LEC autophagy prevents recruitment of tumor-infiltrating T and natural killer cells and abrogates response to immunotherapy. Thus, an LEC-autophagy program boosts immune-checkpoint responses by guiding systemic T cell dynamics.
Subject(s)
Autophagy , Immune Checkpoint Inhibitors , Lymph Nodes , Sphingosine/analogs & derivatives , T-Lymphocytes , Autophagy/drug effects , Animals , Lymph Nodes/immunology , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Mice , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Mice, Inbred C57BL , Autophagy-Related Protein 5/metabolism , Autophagy-Related Protein 5/genetics , Endothelial Cells/metabolism , Sphingosine/pharmacology , Sphingosine/metabolism , Humans , Lysophospholipids/metabolism , Immunotherapy/methods , Cell MovementABSTRACT
An important challenge in the real-world management of patients with advanced clear-cell renal cell carcinoma (aRCC) is determining who might benefit from immune checkpoint blockade (ICB). Here we performed a comprehensive multiomics mapping of aRCC in the context of ICB treatment, involving discovery analyses in a real-world data cohort followed by validation in independent cohorts. We cross-connected bulk-tumor transcriptomes across >1,000 patients with validations at single-cell and spatial resolutions, revealing a patient-specific crosstalk between proinflammatory tumor-associated macrophages and (pre-)exhausted CD8+ T cells that was distinguished by a human leukocyte antigen repertoire with higher preference for tumoral neoantigens. A cross-omics machine learning pipeline helped derive a new tumor transcriptomic footprint of neoantigen-favoring human leukocyte antigen alleles. This machine learning signature correlated with positive outcome following ICB treatment in both real-world data and independent clinical cohorts. In experiments using the RENCA-tumor mouse model, CD40 agonism combined with PD1 blockade potentiated both proinflammatory tumor-associated macrophages and CD8+ T cells, thereby achieving maximal antitumor efficacy relative to other tested regimens. Thus, we present a new multiomics and spatial map of the immune-community architecture that drives ICB response in patients with aRCC.
Subject(s)
CD8-Positive T-Lymphocytes , Carcinoma, Renal Cell , HLA Antigens , Immunotherapy , Kidney Neoplasms , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/therapy , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Humans , Kidney Neoplasms/immunology , Kidney Neoplasms/therapy , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Animals , Immunotherapy/methods , CD8-Positive T-Lymphocytes/immunology , Mice , HLA Antigens/immunology , HLA Antigens/genetics , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Machine Learning , CD40 Antigens/immunology , CD40 Antigens/genetics , Tumor-Associated Macrophages/immunology , Transcriptome , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , FemaleABSTRACT
BACKGROUND: Uterine leiomyosarcomas (uLMS) are aggressive tumours with poor prognosis and limited treatment options. Although immune checkpoint blockade (ICB) has proven effective in some 'challenging-to-treat' cancers, clinical trials showed that uLMS do not respond to ICB. Emerging evidence suggests that aberrant PI3K/mTOR signalling can drive resistance to ICB. We therefore explored the relevance of the PI3K/mTOR pathway for ICB treatment in uLMS and explored pharmacological inhibition of this pathway to sensitise these tumours to ICB. METHODS: We performed an integrated multiomics analysis based on TCGA data to explore the correlation between PI3K/mTOR dysregulation and immune infiltration in 101 LMS. We assessed response to PI3K/mTOR inhibitors in immunodeficient and humanized uLMS patient-derived xenografts (PDXs) by evaluating tumour microenvironment modulation using multiplex immunofluorescence. We explored response to single-agent and a combination of PI3K/mTOR inhibitors with PD-1 blockade in humanized uLMS PDXs. We mapped intratumoural dynamics using single-cell RNA/TCR sequencing of serially collected biopsies. RESULTS: PI3K/mTOR over-activation (pS6high) associated with lymphocyte depletion and wound healing immune landscapes in (u)LMS, suggesting it contributes to immune evasion. In contrast, PI3K/mTOR inhibition induced profound tumour microenvironment remodelling in an ICB-resistant humanized uLMS PDX model, fostering adaptive anti-tumour immune responses. Indeed, PI3K/mTOR inhibition induced macrophage repolarisation towards an anti-tumourigenic phenotype and increased antigen presentation on dendritic and tumour cells, but also promoted infiltration of PD-1+ T cells displaying an exhausted phenotype. When combined with anti-PD-1, PI3K/mTOR inhibition led to partial or complete tumour responses, whereas no response to single-agent anti-PD-1 was observed. Combination therapy reinvigorated exhausted T cells and induced clonal hyper-expansion of a cytotoxic CD8+ T-cell population supported by a CD4+ Th1 niche. CONCLUSIONS: Our findings indicate that aberrant PI3K/mTOR pathway activation contributes to immune escape in uLMS and provides a rationale for combining PI3K/mTOR inhibition with ICB for the treatment of this patient population.