Abstract
Novel treatments based upon the use of immune checkpoint inhibitors have an impressive efficacy in different types of cancer. Unfortunately, most patients do not derive benefit or lasting responses, and the reasons for the lack of therapeutic success are not known. Over the past two decades, a pressing need to deeply profile either the tumor microenvironment or cells responsible for the immune response has led investigators to integrate data obtained from traditional approaches with those obtained with new, more sophisticated, single-cell technologies, including high parameter flow cytometry, single-cell sequencing and high resolution imaging. The introduction and use of these technologies had, and still have a prominent impact in the field of cancer immunotherapy, allowing delving deeper into the molecular and cellular crosstalk between cancer and immune system, and fostering the identification of predictive biomarkers of response. In this review, besides the molecular and cellular cancer-immune system interactions, we are discussing how cutting-edge single-cell approaches are helping to point out the heterogeneity of immune cells in the tumor microenvironment and in blood.
Highlights
Immune checkpoints are critical regulators of the immune system which modulate the duration and amplitude of immune responses to maintain self-tolerance and prevent autoimmunity
An additional layer of complexity originates from the fact that T cells, which are the main mediator of anti-tumor immunity, are extremely heterogenous in the tumor microenvironment (TME), and that beyond T cells many other types of immune cells are present in the tumor tissue that could affect response to immune checkpoint inhibitors (ICI) [4]
A study performed on freshly isolated metastatic melanoma samples from two cohorts of 20 patients used flow cytometry alone to show that an increased fraction of tumor-infiltrating CD8+ T cells expressing high level of PD-1 and CTLA-4 strongly correlated with response to therapy and progression-free survival [133]
Summary
Immune checkpoints are critical regulators of the immune system which modulate the duration and amplitude of immune responses to maintain self-tolerance and prevent autoimmunity. Over the past years, accumulating evidences, both from murine models and clinical epidemiology, have validated the concept of cancer immunosurveillance, demonstrating that the immune response acts as a barrier to tumor development and progression, and is a critical determinant of susceptibility to tumors [8,9,10,11,12,13] This action is exerted through at least three distinct mechanisms: (i) protection of the host from viral infections, and suppression of tumors of viral etiology; (ii) prevention or resolution of inflammation, which facilitates tumorigenesis; (iii) identification and elimination of cancer cells, in certain tissues and on the basis of the expression of tumorspecific antigens [14]. Responses to immune checkpoint monotherapies were not as impressive as in melanoma This means that despite considerable advancements in clinical care of some tumors, epidemiologic data and ongoing clinical trials suggest that most of the patients receiving ICI do not derive benefit or durable responses, and the mechanisms at the basis of this lack of responsiveness are multiple and still not completely known. Single-cell RNA sequencing (scRNA-seq) technology provide a transformative view of cell-type-specific gene expression and allows to analyze hundreds of messenger RNAs (mRNAs) in a single experiment, enabling the reconstruction of a highresolution map of cells according to their molecular signature
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