Thyroid dysfunctions secondary to cancer immunotherapy

Chalan, Paulina; Dalmazi, Giulia Di; Pani, Filippo Eros; Remigis, Alessandra De; Corsello, Andrea; Caturegli, Patrizio

doi:10.1007/s40618-017-0778-8

Cited by 69 publications

(43 citation statements)

References 101 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hyperthyroidism irAEs are often detected before hypothyroidism, but at lower rates than hypothyroidism in patients treated with cancer immunotherapy, including atezolizumab. 41 We found that carrying a single risk allele was sufficient to increase individual risk of hyperthyroidism ( figure 5A ; univariable p=0.0072; HR=1.89; 95% CI 1.19 to 3.02). In contrast, patients homozygous for the risk allele of rs2476601 were more likely to develop atezolizumab-induced hypothyroidism than heterozygous carriers and non-carriers ( figure 5B ; univariable p=0.0029; HR=4.89; 95% CI 1.72 to 13.91).…”

Section: Resultsmentioning

confidence: 76%

Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy

Cubas¹,

Khan²,

Gong³

et al. 2020

J Immunother Cancer

View full text Add to dashboard Cite

BackgroundCancer immunotherapy has evolved from interferon-alpha (IFNα) and interleukin-2 in the 1980s to CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While the search for novel immunomodulatory pathways continues, combination therapies augmenting multiple pathways can also increase efficacy. The association of autoimmune-related adverse events with clinical efficacy following CPI treatment has been inferred and suggests that breaking tolerance thresholds associated with autoimmunity may affect host immune responses for effective cancer immunotherapy.ResultsHere, we show that loss of autoimmune associated PTPN22, a key desensitization node for multiple signaling pathways, including IFNα receptor (IFNAR) and T-cell receptor, can augment tumor responses. Implantation of syngeneic tumors in Ptpn22-/- mice led to expansion and activation of peripheral and intratumoral T cells and, in turn, spontaneous tumor regression as well as enhanced responses in combination with anti-PD-L1 treatment. Using genetically modified mice expressing a catalytically inactive PTPN22 or the autoimmunity-associated human single-nucleotide polymorphism variant, augmentation of antitumor immunity was dependent on PTPN22 phosphatase activity and partially on its adaptor functions. Further, antitumor responses were dependent on both CD4+ and CD8+T cells and, in part, IFNAR function. Finally, we demonstrate that the autoimmune susceptibility Ptpn22(C1858T) variant is associated with lower risk of developing non-melanoma skin cancers, improved overall survival and increased risk for development of hyperthyroidism or hypothyroidism following atezolizumab (anti-PD-L1) treatment.ConclusionsTogether, these data suggest that inhibition of PTPN22 phosphatase activity may provide an effective therapeutic option for cancer immunotherapy and that exploring genetic variants that shift immune tolerance thresholds may serve as a paradigm for finding new cancer immunotherapy targets.

show abstract

Section: Resultsmentioning

confidence: 76%

Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy

Cubas¹,

Khan²,

Gong³

et al. 2020

J Immunother Cancer

View full text Add to dashboard Cite

show abstract

“…This mechanism of action is different from other drug‐induced AIHA where a drug (often a cephalosporin) is absorbed to the red blood cell membrane which then triggers the development of autoantibodies to the red cell membrane, or when a drug neoantigen cross reacts with a red cell antigen (for example methyl dopa) . It is speculated that CPIs cause a random activation of the immune system resulting in the formation of autoantibodies, activation of T‐cell clones, and diminishing the function of regulatory T cells . AIHA is not the only yet rare hematologic complication of CPIs.…”

Section: Discussionmentioning

confidence: 99%

“…31,32 It is speculated that CPIs cause a random activation of the immune system resulting in the formation of autoantibodies, activation of T-cell clones, and diminishing the function of regulatory T cells. 33 AIHA is not the only yet rare hematologic complication of CPIs. Several cases of autoimmune neutropenia, thrombocytopenia, and even pancytopenia were recently published.…”

Section: Discussionmentioning

confidence: 99%

Autoimmune hemolytic anemia associated with the use of immune checkpoint inhibitors for cancer: 68 cases from the Food and Drug Administration database and review

Tanios

Doley

Munker

2018

European J of Haematology

View full text Add to dashboard Cite

Background Immune checkpoint inhibitors (CPI) are widely used in modern oncology and have improved the prognosis of lung cancer, malignant melanoma, and other malignancies. Unlike cytotoxic chemotherapy, drugs such as nivolumab, pembrolizumab, and ipilimumab are associated with immune‐related adverse effects. We recently observed a patient with lung cancer who developed a fulminant warm antibody autoimmune hemolytic anemia (AIHA). Objectives Investigate the frequency and prognosis of AIHA secondary to CPI in a public database and review the literature. Results A total of 68 cases were identified in the database of the Food and Drug Administration (FDA), 43 were associated with nivolumab, 13 with pembrolizumab, seven with ipilimumab, and five with atezolizumab. All episodes of AIHA were listed as serious. If the total number of adverse events cases reported to the FDA is taken as a reference, AIHA is rare, but occurred more frequently with PD‐1 or PD‐L1 targeting agents (0.15%‐0.25%) than with CTLA‐4 inhibitors (0.06%). In addition to our case, the literature review identified 11 similar cases. Most cases of AIHA responded to steroids, but two of 12 were fatal. Conclusion We describe AIHA as a new and serious immune‐related side effect of CPI. Early aggressive management is necessary.

show abstract

“…Given the high mutation burden associated with increased immunogenicity, immunotherapy with immune checkpoint inhibitors has been utilized for advanced and metastatic HTCs. The monoclonal antibodies against programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1), and cytotoxic T lymphocyte associated antigen 4 (CTLA-4), have been utilized either as monotherapies or combination therapies [81]. Clinical trials which are focused on combination therapies for HTC include targeting the immunological landscape of HTC along with tumor angiogenesis, tyrosine kinase receptors, and overactive mTOR signaling.…”

Section: Targeted Therapies For Htcmentioning

confidence: 99%

The Molecular Landscape of Hürthle Cell Thyroid Cancer Is Associated with Altered Mitochondrial Function—A Comprehensive Review

Kumari

Adewale

Kłubo-Gwieździńska

2020

Cells

View full text Add to dashboard Cite

Hürthle cell thyroid carcinoma (HTC) accounts for 3–5% of all thyroid malignancies. Widely invasive HTC is characterized by poor prognosis and limited responsiveness to standard therapy with radioiodine. The molecular landscape of HTC is significantly different from the genetic signature seen in other forms of thyroid cancer. We performed a comprehensive literature review on the association between the molecular features of HTC and cancer metabolism. We searched the Pubmed, Embase, and Medline databases for clinical and translational studies published between 1980 and 2020 in English, coupling “HTC” with the following keywords: “genomic analysis”, “mutations”, “exome sequencing”, “molecular”, “mitochondria”, “metabolism”, “oxidative phosphorylation”, “glycolysis”, “oxidative stress”, “reactive oxygen species”, and “oncogenes”. HTC is characterized by frequent complex I mitochondrial DNA mutations as early clonal events. This genetic signature is associated with the abundance of malfunctioning mitochondria in cancer cells. HTC relies predominantly on aerobic glycolysis as a source of energy production, as oxidative phosphorylation-related genes are downregulated. The enhanced glucose utilization by HTC is used for diagnostic purposes in the clinical setting for the detection of metastases by fluorodeoxyglucose positron emission tomography (FGD-PET/CT) imaging. A comprehensive metabolomic profiling of HTC in association with its molecular landscape might be necessary for the implementation of tumor-specific therapeutic approaches.

show abstract

Thyroid dysfunctions secondary to cancer immunotherapy

Cited by 69 publications

References 101 publications

Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy

Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy

Autoimmune hemolytic anemia associated with the use of immune checkpoint inhibitors for cancer: 68 cases from the Food and Drug Administration database and review

The Molecular Landscape of Hürthle Cell Thyroid Cancer Is Associated with Altered Mitochondrial Function—A Comprehensive Review

Contact Info

Product

Resources

About