Advances in single-cell proteomics technologies have resulted in high-dimensional datasets comprising millions of cells that are capable of answering key questions about biology and disease. The advent of these technologies has prompted the development of computational tools to process and visualize the complex data. In this review, we outline the steps of single-cell and spatial proteomics analysis pipelines. In addition to describing available methods, we highlight benchmarking studies that have identified advantages and pitfalls of the currently available computational toolkits. As these technologies continue to advance, robust analysis tools should be developed in tandem to take full advantage of the potential biological insights provided by these data. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 6 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Even in patients whose tumours exhibit increased T cell infiltration, resistance to immune checkpoint inhibitor (ICI) therapy is common. We investigated mechanisms of ICI resistance using engineered mouse models with increased neoantigen burden and T cell infiltration. We found that in ICI-resistant tumours, T cells upregulate an NF-kB-driven inflammatory circuit in the tumour microenvironment (TME), culminating in PMN-MDSC recruitment and tumour escape. This resistance circuit was molecularly driven by IL-1, TNFa, and G-CSF, and their genetic or pharmacologic inhibition increased ICI efficacy. Furthermore, we identified a subset of human TNF-expressing T cells that expand following ICI therapy and are associated with increased tumour NF-kB signaling. These data reveal a surprising mechanism of ICI resistance whereby T cells instruct NF-kB-mediated inflammation to paradoxically drive a resistance circuit in participating tumours, refining our understanding of ICI response and resistance with important therapeutic implications.

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