Mechanisms of resistance to immune checkpoint inhibitors
Top Cited Papers
Open Access
- 2 January 2018
- journal article
- review article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 118 (1), 9-16
- https://doi.org/10.1038/bjc.2017.434
Abstract
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.Keywords
This publication has 85 references indexed in Scilit:
- Rational combinations of immunotherapeutics that target discrete pathwaysJournal for ImmunoTherapy of Cancer, 2013
- Up-Regulation of PD-L1, IDO, and T regs in the Melanoma Tumor Microenvironment Is Driven by CD8 + T CellsScience Translational Medicine, 2013
- Progenitor and Terminal Subsets of CD8 + T Cells Cooperate to Contain Chronic Viral InfectionScience, 2012
- The blockade of immune checkpoints in cancer immunotherapyNature Reviews Cancer, 2012
- Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune EscapeCancer Research, 2012
- Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunityThe Journal of Experimental Medicine, 2010
- Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockadeProceedings of the National Academy of Sciences of the United States of America, 2008
- PD-1 and Its Ligands in Tolerance and ImmunityAnnual Review of Immunology, 2008
- Shaping and reshaping CD8+ T-cell memoryNature Reviews Immunology, 2008
- Boosting antitumor responses of T lymphocytes infiltrating human prostate cancersThe Journal of Experimental Medicine, 2005