ABSTRACT
Esophageal squamous cell carcinomas (ESCCs) harbor recurrent chromosome 3q amplifications that target the transcription factor SOX2. Beyond its role as an oncogene in ESCC, SOX2 acts in development of the squamous esophagus and maintenance of adult esophageal precursor cells. To compare Sox2 activity in normal and malignant tissue, we developed engineered murine esophageal organoids spanning normal esophagus to Sox2-induced squamous cell carcinoma and mapped Sox2 binding and the epigenetic and transcriptional landscape with evolution from normal to cancer. While oncogenic Sox2 largely maintains actions observed in normal tissue, Sox2 overexpression with p53 and p16 inactivation promotes chromatin remodeling and evolution of the Sox2 cistrome. With Klf5, oncogenic Sox2 acquires new binding sites and enhances activity of oncogenes such as Stat3. Moreover, oncogenic Sox2 activates endogenous retroviruses, inducing expression of double-stranded RNA and dependence on the RNA editing enzyme ADAR1. These data reveal SOX2 functions in ESCC, defining targetable vulnerabilities.
Subject(s)
Adenosine Deaminase/metabolism , Epigenome , Esophageal Neoplasms/genetics , Esophageal Squamous Cell Carcinoma/genetics , RNA-Binding Proteins/metabolism , SOXB1 Transcription Factors/metabolism , 3' Untranslated Regions/genetics , Animals , Base Sequence , Carcinogenesis/genetics , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Endogenous Retroviruses/genetics , Enhancer Elements, Genetic/genetics , Gene Expression Regulation, Neoplastic , Genome, Human , Humans , Interferons/metabolism , Introns/genetics , Kruppel-Like Transcription Factors/genetics , Mice , Organoids/pathology , Protein Binding , RNA, Double-Stranded/metabolism , SOXB1 Transcription Factors/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8+ tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8+ TILs include a subpopulation of 'progenitor exhausted' cells that retain polyfunctionality, persist long term and differentiate into 'terminally exhausted' TILs. Consequently, progenitor exhausted CD8+ TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8+ T cells might be an important component of improving the response to checkpoint blockade.
Subject(s)
Antibodies, Blocking/pharmacology , CD8-Positive T-Lymphocytes/drug effects , Lymphocytes, Tumor-Infiltrating/drug effects , Melanoma, Experimental/prevention & control , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Animals , Antibodies, Blocking/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Cell Line, Tumor , Female , Humans , Lymphocyte Subsets/drug effects , Lymphocyte Subsets/immunology , Lymphocyte Subsets/virology , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/virology , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/prevention & control , Lymphocytic Choriomeningitis/virology , Lymphocytic choriomeningitis virus/drug effects , Lymphocytic choriomeningitis virus/immunology , Lymphocytic choriomeningitis virus/physiology , Melanoma, Experimental/immunology , Melanoma, Experimental/virology , Mice, Congenic , Mice, Inbred C57BL , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Receptor/metabolismABSTRACT
Most patients with cancer either do not respond to immune checkpoint blockade or develop resistance to it, often because of acquired mutations that impair antigen presentation. Here we show that loss of function of the RNA-editing enzyme ADAR1 in tumour cells profoundly sensitizes tumours to immunotherapy and overcomes resistance to checkpoint blockade. In the absence of ADAR1, A-to-I editing of interferon-inducible RNA species is reduced, leading to double-stranded RNA ligand sensing by PKR and MDA5; this results in growth inhibition and tumour inflammation, respectively. Loss of ADAR1 overcomes resistance to PD-1 checkpoint blockade caused by inactivation of antigen presentation by tumour cells. Thus, effective anti-tumour immunity is constrained by inhibitory checkpoints such as ADAR1 that limit the sensing of innate ligands. The induction of sufficient inflammation in tumours that are sensitized to interferon can bypass the therapeutic requirement for CD8+ T cell recognition of cancer cells and may provide a general strategy to overcome immunotherapy resistance.
