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Phagocytosis checkpoints as new targets for cancer immunotherapy.

ABSTRACT: Cancer immunotherapies targeting adaptive immune checkpoints have substantially improved patient outcomes across multiple metastatic and treatment-refractory cancer types. However, emerging studies have demonstrated that innate immune checkpoints, which interfere with the detection and clearance of malignant cells through phagocytosis and suppress innate immune sensing, also have a key role in tumour-mediated immune escape and might, therefore, be potential targets for cancer immunotherapy. Indeed, preclinical studies and early clinical data have established the promise of targeting phagocytosis checkpoints, such as the CD47-signal-regulatory protein ? (SIRP?) axis, either alone or in combination with other cancer therapies. In this Review, we highlight the current understanding of how cancer cells evade the immune system by disrupting phagocytic clearance and the effect of phagocytosis checkpoint blockade on induction of antitumour immune responses. Given the role of innate immune cells in priming adaptive immune responses, an improved understanding of the tumour-intrinsic processes that inhibit essential immune surveillance processes, such as phagocytosis and innate immune sensing, could pave the way for the development of highly effective combination immunotherapy strategies that modulate both innate and adaptive antitumour immune responses.

SUBMITTER: Feng M

PROVIDER: S-EPMC7002027 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Phagocytosis checkpoints as new targets for cancer immunotherapy.

Feng Mingye M Jiang Wen W Kim Betty Y S BYS Zhang Cheng Cheng CC Fu Yang-Xin YX Fu Yang-Xin YX Weissman Irving L IL

Nature reviews. Cancer 20190828 10

Cancer immunotherapies targeting adaptive immune checkpoints have substantially improved patient outcomes across multiple metastatic and treatment-refractory cancer types. However, emerging studies have demonstrated that innate immune checkpoints, which interfere with the detection and clearance of malignant cells through phagocytosis and suppress innate immune sensing, also have a key role in tumour-mediated immune escape and might, therefore, be potential targets for cancer immunotherapy. Inde ...[more]

PMID: 31462760

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Project description:Immune checkpoints are small molecules expressed by immune cells that play critical roles in maintaining immune homeostasis. Targeting the immune checkpoints cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) with inhibitory antibodies has demonstrated effective and durable antitumor activity in subgroups of patients with cancer. The US Food and Drug Administration has approved several immune checkpoint inhibitors (ICPis) for the treatment of a broad spectrum of malignancies. Endocrinopathies have emerged as one of the most common immune-related adverse events (irAEs) of ICPi therapy. Hypophysitis, thyroid dysfunction, insulin-deficient diabetes mellitus, and primary adrenal insufficiency have been reported as irAEs due to ICPi therapy. Hypophysitis is particularly associated with anti-CTLA-4 therapy, whereas thyroid dysfunction is particularly associated with anti-PD-1 therapy. Diabetes mellitus and primary adrenal insufficiency are rare endocrine toxicities associated with ICPi therapy but can be life-threatening if not promptly recognized and treated. Notably, combination anti-CTLA-4 and anti-PD-1 therapy is associated with the highest incidence of ICPi-related endocrinopathies. The precise mechanisms underlying these endocrine irAEs remain to be elucidated. Most ICPi-related endocrinopathies occur within 12 weeks after the initiation of ICPi therapy, but several have been reported to develop several months to years after ICPi initiation. Some ICPi-related endocrinopathies may resolve spontaneously, but others, such as central adrenal insufficiency and primary hypothyroidism, appear to be persistent in most cases. The mainstay of management of ICPi-related endocrinopathies is hormone replacement and symptom control. Further studies are needed to determine (i) whether high-dose corticosteroids in the treatment of ICPi-related endocrinopathies preserves endocrine function (especially in hypophysitis), and (ii) whether the development of ICPi-related endocrinopathies correlates with tumor response to ICPi therapy.

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Phagocytosis checkpoints as new targets for cancer immunotherapy.

Publications

Phagocytosis checkpoints as new targets for cancer immunotherapy.

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