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Advances in PET imaging of cancer

Molecular imaging has experienced enormous advancements in the areas of imaging technology, imaging probe and contrast development, anddata quality, as well as machine learning-based data analysis. Positron emission tomography (PET) and its combination with computed tomography (CT) or magnetic resonance imaging (MRI) as a multimodality PET-CT or PET-MRI system offer a wealth of molecular, functional and morphological data with a single patient scan. Despite the recent technical advances and the availability of dozens of disease-specific contrast and imaging probes, only a few parameters, such as tumour size or the mean tracer uptake, are used for the evaluation of images in clinical practice. Multiparametric in vivo imaging data not only arehighly quantitative but also canprovide invaluable information about pathophysiology, receptor expression, metabolism, or morphological and functional features of tumours, such as pH, oxygenation or tissue density, as well as pharmacodynamic properties of drugs, to measure drug response with a contrast agent. It can further quantitatively map and spatially resolve the intertumoural and intratumoural heterogeneity, providing insights into tumour vulnerabilities for target-specific therapeutic interventions. Failure to exploit and integrate the full potential of such powerful imaging data may lead to a lost opportunity in which patients do not receive the best possible care. With the desire to implement personalized medicine in the cancer clinic, the full comprehensive diagnostic power of multiplexed imaging should be utilized.

The journey from melanocytes to melanoma

Over the past decade, melanoma has led the field in new cancer treatments, with impressive gains in on-treatment survival but more modest improvements in overall survival. Melanoma presents heterogeneity and transcriptional plasticity that recapitulates distinct melanocyte developmental states and phenotypes, allowing it to adapt to and eventually escape even the most advanced treatments. Despite remarkable advances in our understanding of melanoma biology and genetics, the melanoma cell of origin is still fiercely debated because both melanocyte stem cells and mature melanocytes can be transformed. Animal models and high-throughput single-cell sequencing approaches have opened new opportunities to address this question. Here, we discuss the melanocytic journey from the neural crest, where they emerge as melanoblasts, to the fully mature pigmented melanocytes resident in several tissues. We describe a new understanding of melanocyte biology and the different melanocyte subpopulations and microenvironments they inhabit, and how this provides unique insights into melanoma initiation and progression. We highlight recent findings on melanoma heterogeneity and transcriptional plasticity and their implications for exciting new research areas and treatment opportunities. The lessons from melanocyte biology reveal how cells that are present to protect us from the damaging effects of ultraviolet radiation reach back to their origins to become a potentially deadly cancer.

Dynamics and specificities of T cells in cancer immunotherapy

Recent advances in cancer immunotherapy - ranging from immune-checkpoint blockade therapy to adoptive cellular therapy and vaccines - have revolutionized cancer treatment paradigms, yet the variability in clinical responses to these agents has motivated intense interest in understanding how the T cell landscape evolves with respect to response to immune intervention. Over the past decade, the advent of multidimensional single-cell technologies has provided the unprecedented ability to dissect the constellation of cell states of lymphocytes within a tumour microenvironment. In particular, the rapidly expanding capacity to definitively link intratumoural phenotypes with the antigen specificity of T cells provided by T cell receptors (TCRs) has now made it possible to focus on investigating the properties of T cells with tumour-specific reactivity. Moreover, the assessment of TCR clonality has enabled a molecular approach to track the trajectories, clonal dynamics and phenotypic changes of antitumour T cells over the course of immunotherapeutic intervention. Here, we review the current knowledge on the cellular states and antigen specificities of antitumour T cells and examine how fine characterization of T cell dynamics in patients has provided meaningful insights into the mechanisms underlying effective cancer immunotherapy. We highlight those T cell subsets associated with productive T cell responses and discuss how diverse immunotherapies might leverage the pre-existing tumour-reactive T cell pool or instruct de novo generation of antitumour specificities. Future studies aimed at elucidating the factors associated with the elicitation of productive antitumour T cell immunity are anticipated to instruct the design of more efficacious treatment strategies.

The neural addiction of cancer

The recently uncovered key role of the peripheral and central nervous systems in controlling tumorigenesis and metastasis has opened a new area of research to identify innovative approaches against cancer. Although the 'neural addiction' of cancer is only partially understood, in this Perspective we discuss the current knowledge and perspectives on peripheral and central nerve circuitries and brain areas that can support tumorigenesis and metastasis and the possible reciprocal influence that the brain and peripheral tumours exert on one another. Tumours can build up local autonomic and sensory nerve networks and are able to develop a long-distance relationship with the brain through circulating adipokines, inflammatory cytokines, neurotrophic factors or afferent nerve inputs, to promote cancer initiation, growth and dissemination. In turn, the central nervous system can affect tumour development and metastasis through the activation or dysregulation of specific central neural areas or circuits, as well as neuroendocrine, neuroimmune or neurovascular systems. Studying neural circuitries in the brain and tumours, as well as understanding how the brain communicates with the tumour or how intratumour nerves interplay with the tumour microenvironment, can reveal unrecognized mechanisms that promote cancer development and progression and open up opportunities for the development of novel therapeutic strategies. Targeting the dysregulated peripheral and central nervous systems might represent a novel strategy for next-generation cancer treatment that could, in part, be achieved through the repurposing of neuropsychiatric drugs in oncology.