Mechanisms of resistance to immune checkpoint inhibitors

By Russell W. Jenkins, D. Barbie, K. Flaherty. British Journal of Cancer, 2018

1,222 citations recorded by the source corpus.

Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have shown unprecedented clinical activity in several types of cancer and are rapidly transforming the practice of medical oncology. Whereas cytotoxic chemotherapy and small molecule inhibitors (‘targeted therapies’) largely act on cancer cells directly, immune checkpoint inhibitors reinvigorate anti-tumour immune responses by disrupting co-inhibitory T-cell signalling. While resistance routinely develops in patients treated with conventional cancer therapies and targeted therapies, durable responses suggestive of long-lasting immunologic memory are commonly seen in large subsets of patients treated with ICI. However, initial response appears to be a binary event, with most non-responders to single-agent ICI therapy progressing at a rate consistent with the natural history of disease. In addition, late relapses are now emerging with longer follow-up of clinical trial populations, suggesting the emergence of acquired resistance. As robust biomarkers to predict clinical response and/or resistance remain elusive, the mechanisms underlying innate (primary) and acquired (secondary) resistance are largely inferred from pre-clinical studies and correlative clinical data. Improved understanding of molecular and immunologic mechanisms of ICI response (and resistance) may not only identify novel predictive and/or prognostic biomarkers, but also ultimately guide optimal combination/sequencing of ICI therapy in the clinic. Here we review the emerging clinical and pre-clinical data identifying novel mechanisms of innate and acquired resistance to immune checkpoint inhibition.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/055b43f2e45954c829d2dafe5483cf81d2d8a6b3

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Citations in the corpus

• Next generation of immune checkpoint therapy in cancer: new developments and challenges (2018, background): “mechanisms will assist with the process of designing new strategies to overcome resistance and provide the rationale for combination of different forms of immunotherapy [145, 147].”
• Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “Notably, anti-PD-1/PD-L1 immunotherapy can effectively block the PD-1/PD-L1 signaling pathway, restore T cell activity, enhance anti-tumor immunity, and then eliminate tumor cells [11, 12].”