Anti-nuclear antibody and a granuloma could be biomarkers for iCIs-related hepatitis by anti-PD-1 treatment

Kondo, Yasuteru; Akahira, Jun Ichi; Morosawa, Tatsuki; Toi, Yukihiro; Endo, Akashi; Satio, Hiroaki; Endo, Mareyuki; Sugawara, Shunichi; Tanaka, Yasuhito

doi:10.1038/s41598-022-07770-8

Cited by 5 publications

(4 citation statements)

References 36 publications

(32 reference statements)

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“…The copyright holder for this preprint this version posted August 17, 2023. ; https://doi.org/10.1101/2023.08.17.553694 doi: bioRxiv preprint immune-checkpoint inhibitors (ICIs) like nivolumab or pembrolizumab [22,23,24,25].…”

Section: Discussionmentioning

confidence: 99%

Granulomatous inflammatory responses are elicited in the liver of PD-1 knockout mice byde novogenome mutagenesis

Nagaretnam,

Yoneshige,

Takeuchi

et al. 2023

Preprint

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Aims: programmed death-1 (PD-1) is a negative regulator of immune responses. Upon deletion of PD-1 in mice, symptoms of autoimmunity developed only after they got old. In a model experiment in cancer immunotherapy, PD-1 was shown to prevent cytotoxic T lymphocytes from attacking cancer cells that expressed neoantigens derived from genome mutations. Furthermore, the larger number of genome mutations in cancer cells led to the more robust anti-tumor immune responses after the PD-1 blockade. In order to understand the common molecular mechanisms underlying these findings, we hypothesize that we might have acquired PD-1 during evolution in order to avoid/suppress autoimmune reactions against neoantigens derived from mutations in the genome of aged individuals. Main methods: to test the hypothesis, we introduced random mutations into the genome of young PD-1-/- and PD-1+/+ mice. We employed two different procedures of random mutagenesis: administration of a potent chemical mutagen N-ethyl-N-nitrosourea (ENU) into the peritoneal cavity of mice and deletion of MSH2, which is essential for the mismatch-repair activity in the nucleus and, therefore, for the suppression of accumulation of random mutations in the genome. Key findings: we observed granulomatous inflammatory changes in the liver of the ENU-treated PD-1 knockout (KO) mice, but not in the wild-type (WT) counterparts. Such lesions also developed in the PD-1/MSH2 double KO mice, but not in the MSH2 single KO mice. Significance: the results we obtained support our hypothesis: PD-1 probably functions to avoid/suppress inflammatory responses against neoantigens derived from genome mutations in aged individuals.

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Section: Discussionmentioning

confidence: 99%

Granulomatous inflammatory responses are elicited in the liver of PD-1 knockout mice byde novogenome mutagenesis

Nagaretnam,

Yoneshige,

Takeuchi

et al. 2023

Preprint

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“…The results indicated that for patients treated with nivolumab, positive ANA testing was identified as a risk factor for ICI-related hepatitis (risk ratio 2.133: 95% CI 1.085-4.194: p=0.0281). On the other hand, for patients receiving pembrolizumab, both positive ANA and age were found to be potential risk factors for ICIS-related hepatitis (risk ratios 7.834: 95% CI 1.743-35.21: p=0.0073 and 0.896: 95% CI 0.896: p=0.0050, respectively) [101]. Predicting immunemediated hepatitis is relatively difficult, and primary liver diseases and other causes of liver function abnormalities should be excluded first.…”

Section: Ici-associated Hepatitismentioning

confidence: 99%

Uncovering the flip side of immune checkpoint inhibitors: a comprehensive review of immune-related adverse events and predictive biomarkers

Miao,

Quan,

Tang

et al. 2024

Int. J. Biol. Sci.

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Immune checkpoint inhibitors (ICIs) have generated considerable excitement as a novel class of immunotherapeutic agents due to their remarkable efficacy in treating various types of cancer. However, the widespread use of ICIs has brought about a number of safety concerns, especially the development of immune-related adverse events (irAEs). These serious complications could result in treatment discontinuation and even life-threatening consequences, making it critical to identify high-risk groups and predictive markers of irAEs before initiating therapy. To this end, the current article examines several potential predictive markers of irAEs in important organs affected by ICIs. While retrospective studies have yielded some promising results, limitations such as small sample sizes, variable patient populations, and specific cancer types and ICIs studied make it difficult to generalize the findings. Therefore, prospective cohort studies and real-world investigations are needed to validate the potential of different biomarkers in predicting irAEs risk. Overall, identifying predictive markers of irAEs is a crucial step towards improving patient safety and enhancing the management of irAEs. With ongoing research efforts, it is hoped that more accurate and reliable biomarkers will be identified and incorporated into clinical practice to guide treatment decisions and prevent the development of irAEs in susceptible patients.

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“… 125 The presence of pre-existing antinuclear antibodies along with granulomas on histology may serve as potential markers of ICI-related hepatitis. 126 …”

Section: Etiologymentioning

confidence: 99%

Granulomatous liver diseases

Mironova,

Gopalakrishna,

Rodriguez Franco

et al. 2024

Hepatology Communications

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A granuloma is a discrete collection of activated macrophages and other inflammatory cells. Hepatic granulomas can be a manifestation of localized liver disease or be a part of a systemic process, usually infectious or autoimmune. A liver biopsy is required for the detection and evaluation of granulomatous liver diseases. The prevalence of granulomas on liver biopsy varies from 1% to 15%. They may be an incidental finding in an asymptomatic individual, or they may represent granulomatous hepatitis with potential to progress to liver failure, or in chronic disease, to cirrhosis. This review focuses on pathogenesis, histological features of granulomatous liver diseases, and most common etiologies, knowledge that is essential for timely diagnosis and intervention.

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Anti-nuclear antibody and a granuloma could be biomarkers for iCIs-related hepatitis by anti-PD-1 treatment

Cited by 5 publications

References 36 publications

Granulomatous inflammatory responses are elicited in the liver of PD-1 knockout mice byde novogenome mutagenesis

Granulomatous inflammatory responses are elicited in the liver of PD-1 knockout mice byde novogenome mutagenesis

Uncovering the flip side of immune checkpoint inhibitors: a comprehensive review of immune-related adverse events and predictive biomarkers

Granulomatous liver diseases

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