Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child

Ogishi, Masato; Yang, Rui; Aytekin, Caner; Langlais, David; Bourgey, Mathieu; Khan, Taushif; Ali, Fatima; Rahman, Mahbuba; Delmonte, Ottavia M.; Chrabieh, Maya; Zhang, Peng; Gruber, Conor; Pelham, Simon J.; Spaan, András N.; Rosain, Jérémie; Lei, Wei‐Te; Drutman, Scott; Hellmann, Matthew D.; Callahan, Margaret K.; Adamow, Matthew; Wong, Phillip; Wolchok, Jedd D.; Rao, Geetha; Cindy, S.; Nakajima, Yuka; Yaguchi, Tomonori; Chamoto, Kenji; Williams, S.; Émile, Jean-François; Rozenberg, Flore; Glickman, Michael S.; Rapaport, Franck; Kerner, Gaspard; Allington, Garrett; Tezcan, İlhan; Çağdaş, Deniz; Hoşnut, Ferda Özbay; Doğu, Figen; İkincioğulları, Aydan; Rao, V. Koneti; Kainulainen, Leena; Béziat, Vivien; Bustamante, Jacinta; Vilarinho, Sílvia; Lifton, Richard P.; Boisson, Bertrand; Abel, Laurent; Bogunovic, Dusan; Marr, Nico; Notarangelo, Luigi D.; Tangye, Stuart G.; Honjo, Tasuku; Gros, Philippe; Boisson–Dupuis, Stéphanie; Casanova, Jean‐Laurent

doi:10.1038/s41591-021-01388-5

Cited by 76 publications

(65 citation statements)

References 71 publications

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“…13 With respect to PD-1/PD-L1, PD-1-deficient mice are highly susceptible to TB infection, 14 15 and a case of inherited PD-1 deficiency associating with TB has very recently been reported. 16 Given the emerging evidence of increased infection in patients treated with ICIs and evidence that immune checkpoint deficiency can be associated with recurrent infections, we were interested in evaluating the infectious sequelae of ICI therapy. Furthermore, we aimed to characterise the pattern of these infectious complications to inform future clinical management strategies and the associated research agenda.…”

Section: Consequences Of Natural Immune Checkpoint Loss Of Functionmentioning

confidence: 99%

Infections due to dysregulated immunity: an emerging complication of cancer immunotherapy

Morelli

Fujita

Redelman-Sidi

et al. 2021

Thorax

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Immune checkpoint inhibitors (ICIs) have revolutionised cancer treatment. However, immune-related adverse events (irAEs) are a common side effect which can mimic infection. Additionally, treatment of irAEs with corticosteroids and other immunosuppressant agents can lead to opportunistic infection, which we have classed as immunotherapy infections due to immunosuppression. However, emerging reports demonstrate that some infections can be precipitated by ICIs in the absence of immunosuppressive treatment, in contrast to the majority of reported cases. These infections are characterised by a dysregulated inflammatory immune response, and so we propose they are described as immunotherapy infections due to dysregulated immunity. This review summarises the rapidly emerging evidence of these phenomena and proposes a new framework for considering infection in the context of cancer immunotherapy.

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Section: Consequences Of Natural Immune Checkpoint Loss Of Functionmentioning

confidence: 99%

Infections due to dysregulated immunity: an emerging complication of cancer immunotherapy

Morelli

Fujita

Redelman-Sidi

et al. 2021

Thorax

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“…Recently, a rare, homozygous frameshift mutation (c.105dupC, p.T36Hfs*70) in PDCD1 was identified in a patient with tuberculosis and autoimmunity (96). The mutation was shown to abrogate PD-1 expression.…”

Section: Pdcd1 Deficiencymentioning

confidence: 99%

Inborn Errors of Immunity and Their Phenocopies: CTLA4 and PD-1

Hao

Cook

2022

Front. Immunol.

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Elucidating links between genotype and phenotype in patients with rare inborn errors of immunity (IEIs) provides insights into mechanisms of immune regulation. In many autosomal dominant IEIs, however, variation in expressivity and penetrance result in complex genotype-phenotype relations, while some autosomal recessive IEIs are so rare that it is difficult to draw firm conclusions. Phenocopies arise when an environmental or non-genetic factor replicates a phenotype conferred by a specific genotype. Phenocopies can result from therapeutic antibodies or autoantibodies that target a protein to replicate aspects of the phenotype conferred by mutations in the gene encoding the same protein. Here, we consider IEIs arising from rare genetic variants in CTLA4 and PDCD1 and compare clinical and laboratory manifestations arising as drug-induced phenocopies (immune related adverse events, IRAEs) in cancer patients treated with immune checkpoint inhibitors (ICI) and identify outstanding questions regarding mechanism of disease.

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“…The phenotype of CTLA-4 deficient mice is even more severe, with mice dying from lymphoproliferative syndrome and fatal multiorgan destruction at 4 weeks of age due to defects in Tregs and the absence of key T effector inhibitory pathways [ 94 , 95 ]. In humans, PD-1 deficiency and germline mutations in CTLA-4 increase the susceptibility to infections and autoimmune disorders [ 96 , 97 , 98 , 99 ]. Together, these mouse models and clinical observations have demonstrated the fine balance between immune cell activation and tolerance, governing immune system equilibrium and tissue homeostasis [ 100 , 101 ].…”

Section: Peripheral Immune Tolerance—the Role Of Immune Checkpointsmentioning

confidence: 99%

Immune Checkpoints and Innate Lymphoid Cells—New Avenues for Cancer Immunotherapy

Jacquelot

Ghaedi

Warner

et al. 2021

Cancers

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Immune checkpoints (IC) are broadly characterized as inhibitory pathways that tightly regulate the activation of the immune system. These molecular “brakes” are centrally involved in the maintenance of immune self-tolerance and represent a key mechanism in avoiding autoimmunity and tissue destruction. Antibody-based therapies target these inhibitory molecules on T cells to improve their cytotoxic function, with unprecedented clinical efficacies for a number of malignancies. Many of these ICs are also expressed on innate lymphoid cells (ILC), drawing interest from the field to understand their function, impact for anti-tumor immunity and potential for immunotherapy. In this review, we highlight ILC specificities at different tissue sites and their migration potential upon inflammatory challenge. We further summarize the current understanding of IC molecules on ILC and discuss potential strategies for ILC modulation as part of a greater anti-cancer armamentarium.

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Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child

Cited by 76 publications

References 71 publications

Infections due to dysregulated immunity: an emerging complication of cancer immunotherapy

Infections due to dysregulated immunity: an emerging complication of cancer immunotherapy

Inborn Errors of Immunity and Their Phenocopies: CTLA4 and PD-1

Immune Checkpoints and Innate Lymphoid Cells—New Avenues for Cancer Immunotherapy

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