Tumour-intrinsic resistance to immune checkpoint blockade

By A. Kalbasi, Antoni Ribas. Nature reviews. Immunology, 2019

1,284 citations recorded by the source corpus.

‘Immune checkpoint blockade’ for cancer describes the use of therapeutic antibodies that disrupt negative immune regulatory checkpoints and unleash pre-existing antitumour immune responses. Antibodies targeting the checkpoint molecules cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1) and PD1 ligand 1 (PD-L1) have had early success in the clinic, which has led to approval by the US Food and Drug Administration of multiple agents in several cancer types. Yet, clinicians still have very limited tools to discriminate a priori patients who will and will not respond to treatment. This has fuelled a wave of research into the molecular mechanisms of tumour-intrinsic resistance to immune checkpoint blockade, leading to the rediscovery of biological processes critical to antitumour immunity, namely interferon signalling and antigen presentation. Other efforts have shed light on the immunological implications of canonical cancer signalling pathways, such as WNT–β-catenin signalling, cell cycle regulatory signalling, mitogen-activated protein kinase signalling and pathways activated by loss of the tumour suppressor phosphoinositide phosphatase PTEN. Here we review each of these molecular 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. Understanding why some patients and not others respond to immune checkpoint blockade for cancer is crucial for extending benefit from this therapy. Here the authors describe how tumour cells can resist immune checkpoint blockade, for example, by resistance to interferon signalling and through immune-evasive oncogenic signalling pathways.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/456368a7d265806084c1372ff0cffaa3a38988dc

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In Immunology

1. A. Labani-Motlagh
2. K. Polyak
3. Mehrnoush Ashja-Mahdavi
4. A. Loskog

In Oncology

1. A. Marusyk
2. K. Polyak
3. R. Weinberg
4. Zena Werb
5. D. Hanahan

Citations in the corpus

• Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities (2022, background): “Moreover, phase II clinical trials have demonstrated that decitabine increases cisplatin/carboplatin sensitivity in platinum-resistant ovarian cancer by affecting Wnt/β-catenin pathway.(307) Therefore, the rational use of Wnt signalling pathway inhibitors is of great help to solve the clinical probl”
• The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses (2020, background): “Such mechanisms of resistance were recently reviewed elsewhere (252).”
• Intratumor heterogeneity: the Rosetta stone of therapy resistance (2020, background): “Acquired resistance to immunotherapy can develop due to ITH for neoantigens, antigen presentation, and interferon signaling (Havel et al., 2019; Kalbasi and Ribas, 2019).”