Targeted approaches to bypass defects in IFN signalling and antigen presentation or to inhibit immunosuppressive oncogenic signalling pathways hold promise in broadening the impact of immune checkpoint blockade. Acknowledgements The authors are supported by grants from the Parker Institute for Cancer Immunotherapy (A.R.), the US National Institutes of Health (grant R35 CA197633 to A.R.), the University of California, Los Angeles (CTSI KL2 Award to A.K.), the Sarcoma Alliance for Research Through Collaboration Career Enhancement Program (A.K.) and the Ressler Family Fund (A.R.). Footnotes Competing interests A.K. mechanisms of resistance and explore ongoing approaches to overcome resistance to immune checkpoint blockade and expand the spectrum of patients who can benefit from immune checkpoint blockade. Cancer immunotherapy is a strategy to treat malignancies by leveraging the cytotoxic potential of the human immune system, especially tumour-specific cytotoxic T cells. Among the different types of cancer immunotherapy, immune checkpoint blockade has had the broadest impact, with several antibodies targeting cytotoxic T lymphocyte antigen 4 (CTLA4) or the programmed cell death 1 (PD1)CPD1 ligand 1 (PD-L1) axis approved for use in a number of different cancers. A S107 large number of antibodies and small molecules targeting other putative immune checkpoints (such as LAG3, TIGIT, TIM3, B7H3, CD39, CD73 and adenosine A2A receptor), disrupting unfavorable regulation between tumour cells and T cells, or myeloid cells and T cells, are in clinical S107 and preclinical development. Patient-intrinsic factors (such as age, sex, HLA genotype and genetic polymorphisms), tumour stroma-intrinsic factors (such as the host immune system and tumour-associated stroma) and environmental factors (such as the gut microbiota) may contribute to the success or failure of immune checkpoint blockade1C3. However, tumour cell-intrinsic factors (herein defined as tumour-intrinsic factors), relating to the genetic, transcriptional or functional profile of the tumour cells themselves, are among the main determinants of response and resistance. The importance of tumour-intrinsic factors is reflected in the wide variation of response rates to immune checkpoint blockade across histological types and the high response rates of tumours with comparable molecular and genetic features (for example, microsatellite instability). These tumour-intrinsic factors can also influence the involvement of some tumour cell-extrinsic factors (such as the host immune system and tumour-associated stroma) in therapy resistance. In this Review, we focus on tumour-intrinsic factors of resistance to immune checkpoint blockade. In doing so, we revisit the immunological basis for tumour responses to immune checkpoint blockade, spotlight key biomarkers and discuss how these reflect the tumour-intrinsic factors that promote responsiveness to immune checkpoint blockade. We then look at the mechanisms by which tumour-intrinsic defects can lead to resistance to immune checkpoint blockade and spotlight existing and emerging approaches to overcome tumour-intrinsic mechanisms of resistance. Tumour-intrinsic mechanisms of resistance The factors that determine the induction and maintenance of a naturally occurring antitumour T cell response are complex. Characteristics that are intrinsic to tumour cells themselves such as mutational scenery, function of interferon signalling pathways, expression of antigen-presenting molecules and immune-evasive oncogenic signalling pathways influence the priming, activation and recruitment of T cells to the tumour Rabbit Polyclonal to ACTBL2 microenvironment, which are necessary for an immune response in the context of immune checkpoint blockade. Likewise, resistance to immune checkpoint blockade can result from disruptions in any of these key tumour characteristics, either S107 by preventing a de novo antitumour immune response or by counteracting an ongoing antitumour response. Insufficient tumour antigenicity Several studies have exhibited the potential of tumour neoantigens to serve as effective targets for antitumour immunity, and there is correlation between mutational burden and response to immune checkpoint blockade across malignancies4C6. In a patient who responded to anti-CTLA4 immune checkpoint blockade, it was shown that T cells specific for a particular tumour neoantigen previously existed within the tumour microenvironment and expanded in response to anti-CTLA4 therapy7. In a mouse methylcholanthrene-induced sarcoma model, T cells specific for neoantigens expand and gain antitumour S107 functionality in response to immune checkpoint blockade8. Potent neoantigen-specific T cells can even be detected within the tumour microenvironment in the absence of immune checkpoint blockade. In a patient with metastatic cholangio-carcinoma, tumour-infiltrating lymphocytes harboured a populace of CD4+ T cells specific for a S107 tumour neoantigen. Adoptive transfer of enriched mutation-specific T cells resulted in an effective antitumour response9. The accumulating evidence that neoantigens are key cancer immunogens supports the promising early results of ongoing studies of neoantigen-based tumour vaccines10. The observation that patients with microsatellite instability due to mismatch repair defects have high response rates to immune checkpoint blockade further supports the role of neoantigens in the antitumour immune response. Conversely, tumours with poor antigenicity are less likely to harbour intrinsic sensitivity to immune checkpoint blockade. Tumour-intrinsic interferon- signalling A productive T cell response against a tumour antigen results in the expression of interferon- (IFN) in the tumour microenvironment, which activates Janus.