Skip to main content

Main menu

  • Home
  • About
    • About CBM
    • Editorial Board
  • Articles
    • Ahead of print
    • Current Issue
    • Archive
    • Collections
    • Cover Story
  • For Authors
    • Instructions for Authors
    • Resources
    • Submit a Manuscript
  • For Reviewers
    • Become a Reviewer
    • Instructions for Reviewers
    • Resources
    • Outstanding Reviewer
  • Subscription
  • Alerts
    • Email Alerts
    • RSS Feeds
    • Table of Contents
  • Contact us
  • Other Publications
    • cbm

User menu

  • My alerts

Search

  • Advanced search
Cancer Biology & Medicine
  • Other Publications
    • cbm
  • My alerts
Cancer Biology & Medicine

Advanced Search

 

  • Home
  • About
    • About CBM
    • Editorial Board
  • Articles
    • Ahead of print
    • Current Issue
    • Archive
    • Collections
    • Cover Story
  • For Authors
    • Instructions for Authors
    • Resources
    • Submit a Manuscript
  • For Reviewers
    • Become a Reviewer
    • Instructions for Reviewers
    • Resources
    • Outstanding Reviewer
  • Subscription
  • Alerts
    • Email Alerts
    • RSS Feeds
    • Table of Contents
  • Contact us
  • Follow cbm on Twitter
  • Visit cbm on Facebook
Research ArticleOriginal Article

Ferritin as a diagnostic, differential diagnostic, and prognostic marker for immune-related adverse events

Weihong Zhang, Yuan Meng, Lin Yang, Meng Shen, Li Zhou, Runmei Li, Yang Wang, Weijiao Du, Yanjuan Xiong, Ying Han, Xinwei Zhang, Liang Liu and Xiubao Ren
Cancer Biology & Medicine November 2021, 18 (4) 1109-1117; DOI: https://doi.org/10.20892/j.issn.2095-3941.2021.0037
Weihong Zhang
1Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yuan Meng
1Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lin Yang
2State Key Laboratory of Experimental Hematology, Peking Union Medical College, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin 300020, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Meng Shen
1Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Li Zhou
1Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Runmei Li
1Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yang Wang
1Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Weijiao Du
1Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yanjuan Xiong
1Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ying Han
1Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xinwei Zhang
1Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Liang Liu
1Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Liang Liu
  • For correspondence: [email protected] [email protected]
Xiubao Ren
1Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Xiubao Ren
  • For correspondence: [email protected] [email protected]
  • Article
  • Figures & Data
  • References
  • Info & Metrics
  • PDF
Loading

Abstract

Objective: Distinguishing immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) from the AEs caused by chemotherapy, targeted therapy, or infection is highly difficult. This study offers new insights into evaluating the diagnosis, differential diagnostic, and prognostic value of ferritin for irAEs induced by ICIs.

Methods: From December 1, 2018, to April 1, 2019, we examined 318 patients with malignant tumors who received serum ferritin monitoring. The cohort comprised 231 patients treated with PD-1 inhibitor or combination with chemotherapy, and 87 patients treated with chemotherapy. Of the 231 patients, 90 had irAEs (irAE group), 70 had non-irAEs (non-irAE group), 67 had no AEs (no irAE-non irAE group), and 4 had unclassified AEs. In the 87 patients, 60 had AEs (AE group), and 27 had no AEs (no AE group). Statistical analyses were conducted with nonparametric Mann-Whitney tests.

Results: At the onset of AEs in the irAE group, ferritin (normal range, 35–150 µg/L) rose to a median of 927 µg/L (range, 117–17,825 µg/L) from 86 µg/L at baseline (range, 29–421 µg/L) (P < 0.001). Ferritin levels at the onset of AEs in the irAE group were significantly higher than those in the non-irAE group (median, 81 µg/L; range, 32–478 µg/L) (P < 0.001) and the AE group (median, 103 µg/L; range, 23–712 µg/L) (P < 0.001). After treatment in the irAE group, ferritin continuously decreased to a normal range in recovered patients, showed no significant changes in stable patients, and continued to rise in patients who died.

Conclusions: Ferritin can be used as a diagnostic, differential diagnostic, and prognostic marker for irAEs in patients treated with ICIs.

keywords

  • Ferritin
  • diagnosis
  • prognosis
  • irAEs
  • PD-1
  • chemotherapy

Introduction

Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death 1 receptor (PD-1)/programmedcell death 1 ligand 1 (PD-L1) pathways are influencing new cancer treatment model sand producing unprecedented clinical effects in a wide diversity of cancers, such as melanoma, renal cell carcinoma, lung cancer, urothelial cancer, or head and neck cancer1–6. However, these treatments induce a series of distinct immune-related adverse events (irAEs), which are similar to autoimmune responses. Virtually every organ of the body is affected by irAEs, such as pneumonitis, colitis, endocrinopathies, and hepatitis; rarer adverse effects include myocarditis and neurotoxicity7,8. The gastrointestinal, pulmonary, dermatologic, hepatic, and endocrine systems are thereby frequently affected. The ASCO Clinical Practice Guideline Summary provides system-based toxicity diagnosis and management guidelines, which recommend treatments depending on the affected system. The major treatment for ICI-related AEs is immunosuppression with methylprednisolone8. Because of the adverse effects of steroid-refractory, immunosuppressive effects are in facilitating escalation, including other immunosuppressants like tocilizumab, mycophenolate mofetil, or infliximab8. Although these irAE symptoms are usually reversible and controllable, they often lead to treatment disruption or dose reduction, and/or discontinuation of checkpoint treatment. When new symptoms appear during ICI treatment, other etiological factors such as infections, viral reactivation, tumor progression, or toxicity associated with other drugs must be excluded. Because a host of organ system symptoms are unspecific in irAE, diagnosis and differential diagnosis have become difficult. Especially with a combination of immunotherapy with chemotherapy or targeted therapy, distinguishing irAEs from AEs caused by chemotherapy or targeted therapy is very difficult. The diagnosis and differential diagnosis of irAEs play a major role in the treatment of AE and in subsequent tumor treatment decisions.

Recently, Abolhassani et al.8 have evaluated the value of CRP in diagnosing irAEs through retrospective analysis of the correlations among 88 events of irAEs in 37 patients with melanoma and their serumc-reactive protein (CRP) levels. Elevated CRP was predictive of irAEs in patients without infectious disease who were treated with ICIs. Liudahl and colleagues9 have reported a relationship between enhanced risk of high-grade irAEs in patients treated with ICIs and inchoate therapy-induced changes in circulating B cells. Bamias10 has shown that levels of CRP pre-therapy, combined with IFN-γ and IL-17, may be used to predict irAE development. These study designs were retrospective; therefore, a control group without AEs or with non-irAEs was not included. ICIs combined with chemotherapy or other therapies are increasingly and widely used in tumor treatment, and distinguishing irAEs from the AEs caused by chemotherapy or other treatments will be difficult. Thus, markers for convenient and rapid detection and differentiation of irAEs from infections or other AEs are urgently needed. At present, no effective marker can distinguish irAEs from infections or other AEs. Serum ferritin, a marker of inflammation, infection, and malignancy, continues to be measured in patients with cancer. On October 28, 2018, a patient with adrenal carcinoma and PD-L1 > 50% in tumor tissues received PD-1 inhibitor treatment in our department. After 1 day of treatment, the patient had panic symptoms. Electrocardiography indicated bigeminy with premature ventricular contraction. Myocardial enzyme indexes were abnormally elevated. Serum ferritin increased from 67 µg/L at baseline (normal range, 35–150 µg/L) to 7,680 µg/L. After 3 days, the patient developed heart failure, renal failure, and respiratory failure. The patient was diagnosed with the grade 4 irAE of explosive autoimmune myocarditis and received high-dose methylprednisolone, mycophenolate mofetil, high-dose immunoglobulin, and plasma exchange to treat the irAE. After 30 days of treatment, the patient recovered from the irAE. During the 30 days of treatment for the irAE, ferritin and myocardial enzymes simultaneously decreased to normal levels. Therefore, we wondered whether ferritin might serve as a diagnostic and prognostic indicator of irAE. Consequently, we designed this study to evaluate the diagnostic, differential diagnostic, and prognostic value of ferritin in irAEs induced by ICIs.

Materials and methods

Patients

This study was approved by the Ethical Committee of Tianjin Medical University Cancer Institute and Hospital, according to the guidelines of the Declaration of Helsinki (Approval No. E2016055). Informed consent was obtained from all participants. Patients who were eligible for enrollment were required to meet the following criteria: a diagnosis of solid tumor or acute leukemia; age between 18 and 75 years; treatment with anti-PD-1 antibody (nivolumab, pembrolizumab, sintilimab, or camrelizumab), anti-PD-1 antibody combination with chemotherapy or chemotherapy; and sufficient blood samples to test for serum ferritin levels. Patients were excluded if they had immune deficiency or autoimmune diseases, severe allergic disorder, uncontrollable medical conditions, or infectious diseases such as viral reactivation, colitis, or pneumonia.

AE diagnosis, treatment, and ferritin monitoring

All patients received hemato-biochemistry and imaging examinations at baseline according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and the National Comprehensive Cancer Network Management of Immunotherapy-Related Toxicties version 1, 2018. The changes in hemato-biochemistry and imaging examination were monitored during the entire adverse reaction. Adverse events (AEs) and abnormal laboratory findings were graded on the basis of CTCAE version 4.0 and the National Comprehensive Cancer Network Management of Immunotherapy-Related Toxicties version 1, 2018. If patients who received ICI or an ICI combination with chemotherapy had AEs, the AEs were further diagnosed as irAEs or non-irAEs by a multi-disciplinary team including an oncologist, rheumatologist, immunologist, radiologist, and pathologist. IrAEs were managed by the team throughout the entire treatment process. All patients received serum ferritin monitoring every 3 days, including 3 consecutive tests for patients with no AEs and continuous detection until AE recovery, or up to 10 tests in patients with irAEs or non-irAEs. Patients with irAEs received treatment according to the National Comprehensive Cancer Network Management of Immunotherapy-Related Toxicties version 1, 2018.

Statistical analysis

Statistical differences between uninterrupted ferritin values were calculated with nonparametric Mann-Whitney tests. A 2-sided P value less than 0.05 indicated statistical significance. All calculations were implemented in R software version 3.5.1.

Results

Patient characteristics

From December 1, 2018, to April 1, 2019, 318 patients who met the eligibility criteria received serum ferritin monitoring, including 231 patients treated with PD-1 inhibitor or a combination with chemotherapy, and 87 patients treated with chemotherapy (Table 1). Among the 231 patients, 90 had irAEs (irAE group), 70 had non-irAEs (non-irAE group), 67 had no AEs (no irAE-non-irAE group), and 4 had unclassified AEs. Among the 87 patients, 60 had AEs (AE group), and 27 had no AEs (no AE group). The distribution of age, gender and cancer type among groups is shown in Table 2. The distribution of AE type and grade among groups is shown in Table 3. Among 90 irAEs, 20 patients had grade 1, 41 had grade 2, 23 had grade 3, and 6 had grade 4 irAEs at AE onset. Two patients progressed from grade 1 to grade 2; 72 patients with grade 2, 3, or 4 irAEs received immunosuppressive therapy, including 62 completely recovered patients, 6 stable patients, and 4 patients who died.

View this table:
  • View inline
  • View popup
Table 1

Cancer treatment methods and AE types in patients

View this table:
  • View inline
  • View popup
Table 2

The distribution of age, gender, and cancer type among groups

View this table:
  • View inline
  • View popup
Table 3

Distribution of AE type and grade among groups

Diagnosis

At the onset of 90 irAEs, the ferritin (normal range, 35–150 µg/L) rose to a median of 927 µg/L (range, 117–17,825 µg/L) from 86 µg/L at baseline (range, 29–421 µg/L) (P < 0.001). The ferritin at AE onset in 20 grade 1 irAEs (median, 272 µg/L; range, 117–423 µg/L) was significantly higher than that at baseline in 90 irAEs (P < 0.001). The ferritin at AE onset in 41 grade 2 irAEs (median, 856 µg/L; range, 231–1,879 µg/L) was significantly higher than that in grade 1 irAEs (P < 0.001). In addition, we compared 23 grade 3 irAEs (median, 3,054 µg/L; range, 1,456–7,078 µg/L) with grade 2 irAEs (P < 0.001), and compared 6 grade 4 irAEs (median, 7,260 µg/L; range, 6,754–17,825 µg/L) with grade 3 irAEs (P < 0.001) (Figure 1A). In grade 1 irAEs, the ferritin levels at AE onset were significantly higher than those at baseline (median, 93 µg/L; range, 32–192 µg/L) (P < 0.001) (Figure 1B), and in grade 2 irAEs (Figure 1C), grade 3 irAEs (Figure 1D), and grade 4 irAEs (Figure 1E).

Figure 1
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1

Ferritin values at baseline and AE onset in the irAE group. The bars represent the median and range. (A) Ferritin values at baseline and AE onset for 90 irAEs; ferritin at AE onset for 20 grade 1 irAEs, 41 grade 2 irAEs, 23 grade 3 irAEs, and 6 grade 4 irAEs; (B) ferritin for 20 grade 1 irAEs; (C) ferritin for 41 grade 2 irAEs; (D) ferritin for 23 grade 3 irAEs; (E) ferritin for 6 grade 4 irAEs. ***, P < 0.001.

Differential diagnosis

The ferritin levels at AE onset in the irAE group were significantly higher than those in the non-irAE group (median, 81 µg/L; range, 32–478 µg/L) (P < 0.001) and the AE group (median, 103 µg/L; range, 23–712 µg/L) (P < 0.001) (Figure 2A). The ferritin at AE onset in 16 patients with pneumonia in the irAE group (median, 1,765 µg/L; range, 635–8,134 µg/L) was significantly higher than that of 27 patients with pneumonia in the non-irAE group and AE group (median, 134 µg/L; range, 27–478 µg/L) (P < 0.001) (Figure 2B). In addition, we observed 18 hepatitis cases in the irAE group (median, 3,008 µg/L; range, 902–17,825 µg/L), compared with 23 in the non-irAE group and AE group (median, 86 µg/L; range, 32–298 µg/L) (P < 0.001) (Figure 2C); 14 rash cases in the irAE group (median, 517 µg/L; range, 201–17,825 µg/L) compared with 13 in the non-irAE group and AE group (median, 71 µg/L; range, 33–151 µg/L) (P < 0.001) (Figure 2D); and 13 fever cases in the irAE group (median, 487 µg/L; range, 187–2,899 µg/L) compared with 6 in the non-irAE group and AE group (median, 131 µg/L; range, 63–267 µg/L) (P = 0.002) (Figure 2E).

Figure 2
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2

Ferritin values at baseline and after AE onset among groups. The bars represent the median and range. (A) Ferritin at AE onset in the irAE group; ferritin at baseline and AE onset in the non-irAE group and the AE group; and baseline ferritin in the no irAE-nonir AE group and no AE group; (B) ferritin at AE onset for pneumonia; (C) ferritin at AE onset for hepatitis; (D) ferritin at AE onset for rash; (E) ferritin at AE onset for fever. ***, P < 0.001.

Prognosis

After treatment in the irAE group, the ferritin continuously decreased to a normal range in 62 effective patients (endpoint median, 75 µg/L; range, 34–95 µg/L); no significant changes in ferritin were observed in 4 stable patients (endpoint median, 2,317 µg/L; range, 678–4,770 µg/L); and the ferritin continued to rise in 4 patients who died (endpoint median, 16,954 µg/L; range, 11,217–17,825 µg/L) (Figure 3).

Figure 3
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 3

Changes in ferritin levels after treatment in 62 recovered patients, 6 stable patients, and 4 patients who died.

Discussion

In this study, patients who received ICI therapy, chemotherapy, or ICI therapy plus chemotherapy were included. We analyzed the ferritin levels in patients with irAEs, non-irAEs, AEs caused by chemotherapy, or no AEs to better evaluate the diagnostic, differential diagnostic, and prognostic value of ferritin for irAEs induced by ICIs. The median ferritin at AE onset was significantly higher than the baseline ferritin in patients with irAEs. The median ferritin at AE onset increased with irAE grade, and statistically significant differences were observed among grades. The median ferritin at AE onset for each grade was significantly higher than the baseline ferritin for the corresponding irAE grade. Therefore, ferritin can serve as a predictive and diagnostic marker of irAEs. The median ferritin level at AE onset in patients with irAEs was significantly higher than that in patients with non-irAEs or AEs caused by chemotherapy. The ferritin level at AE onset for the irAEs pneumonia, hepatitis, rash, or fever were significantly higher than those for non-irAEs or AEs caused by chemotherapy. These results showed that the ferritin can serve as a differential diagnostic marker to distinguish irAEs from non-irAEs. After treatment in the irAE group, the ferritin continuously decreased to normal ranges in effective patients, showed no significant changes in stable patients, and continued to rise in patients who died. The change in ferritin levels reflects the therapeutic effects of ICIs on irAEs, thus indicating that ferritin is a prognostic biomarker of irAEs.

The French scientist Laufberger discovered ferritin in 193711. In 1972, Addison et al.12 used immunoradiometric assays and validated the ability to detect ferritin in human serum. In addition, ferritin is secreted by Kupffer cells, hepatocytes, and macrophages13. Although numerous facets of the basic biology of serum ferritin remain unclear, various effects are increasingly being ascribed to extracellular ferritin, including newly discovered effects such as angiogenesis, immunity, cancer, inflammation, iron delivery, and signaling14. According to early in vitro studies, ferritin regulates the body’s immune function by inhibiting the function of lymphocytes15. Lymphocytes are activated by phytohemagglutinin and concanavalin A when human lymphocytes are treated with spleen ferritin16. Subsequently, another in vivo study has shown that ferritin suppresses immunity. Excess iron restrains the function of helper T (CD4) cells, as well as the tumoricidal action of monocytes and macrophages, and influences the distribution of the T-lymphocyte subset17,18. In patients with hereditary hemochromatosis, iron overload decreases the numbers and activity of CD4 cells, and increases the numbers and activity of suppressor T (CD8) cells, thus increasing the CD8:CD4 ratios19. Therefore, excessive iron is thought to damage the monitoring of cancer cells through these mechanisms. Serum ferritin is widely accepted to be a reactant in the acute phase and a marker of acute and chronic inflammation, and it is known to nonspecifically increase in a variety of inflammatory conditions, including chronic kidney disease, rheumatoid arthritis, and acute infection20,21. The elevated ferritin in these states reflects an increase in total iron storage throughout the body, but paradoxically, these stores are isolated and cannot be used for hematopoiesis, a process that leads to inflammatory anemia22. The relative lack of iron in inflammation and malignant tumors is speculated to be a defense mechanism that limits the use of serum iron by pathogens and tumors23. Serum ferritin is elevated in many malignancies18,24. In neuroblastoma, increased serum ferritin is directly associated with the secretion of ferritin through the tumor25. In our study, the ferritin levels in irAEs induced by ICIs were significantly higher than those in non-irAEs or AEs caused by chemotherapy. The mechanism underlying this phenomenon is unclear and requires further research. Studies on the mechanisms of recently emerging viruses—for instance, severe acute respiratory syndrome corona virus, Middle Eastern respiratory syndrome corona virus, and H7N9, which drive hyper cytokinemia and aggressive inflammation that lead to fatal acute lung injury—have shown that activation of the proinflammatory monocyte/macrophage system plays a crucial role in the development of diseases26. The occurrence and development of GVHD are always accompanied by the activation of the monocyte/macrophage system27,28. Whether the monocyte/macrophage system can be activated and secrete large amounts of ferritin, thus increasing serum ferritin levels in irAEs induced by ICIs, as in GVHD and severe viral infection, remains to be determined. These hypotheses must be verified and confirmed through in vitro and in vivo experiments.

Conclusions

In conclusion, our data showed that ferritin can be used as a diagnostic, differential diagnostic, and prognostic marker for irAEs in patients with ICI treatment. The mechanism responsible for higher ferritin levels in irAEs induced by ICI than those in non-irAEs or AEs caused by chemotherapy or other therapy must be further studied.

Grant support

This work was supported by grants from the National Key R&D Program of China (Grant No. 2018YFC1313400), the National Major Scientific and Technological Special Project for “Significant New Drug Development” of China (Grant No. 2018ZX09201-015), and the National Natural Science Foundation of China (Grants Nos. 81872487, 81872166, U20A20375, and 81974416).

Acknowledgements

We thank Professor Shizhen Emily Wang for help in modifying the language of the manuscript. The authors acknowledge all participating patients and their families. We are also thankful to the staff of all institutions involved in this study.

Footnotes

  • ↵*These authors contributed equally to this work.

  • Conflict of interest statement No potential conflicts of interest are disclosed.

  • Received January 13, 2021.
  • Accepted March 30, 2021.
  • Copyright: © 2021, Cancer Biology & Medicine
https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY) 4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

References

  1. 1.↵
    1. Larkin J,
    2. Chiarion-Sileni V,
    3. Gonzalez R,
    4. Grob JJ,
    5. Cowey CL,
    6. Lao CD, et al.
    Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015; 373: 23–34.
    OpenUrlCrossRefPubMed
  2. 2.
    1. Rini BI,
    2. Plimack ER,
    3. Stus V,
    4. Gafanov R,
    5. Hawkins R,
    6. Nosov D, et al.
    Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019; 380: 1116–27.
    OpenUrlCrossRefPubMed
  3. 3.
    1. Gandhi L,
    2. Rodríguez-Abreu D,
    3. Gadgeel S,
    4. Esteban E,
    5. Felip E,
    6. De Angelis F, et al.
    Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018; 378: 2078–92.
    OpenUrlCrossRefPubMed
  4. 4.
    1. Paz-Ares L,
    2. Luft A,
    3. Vicente D,
    4. Tafreshi A,
    5. Gümüş M,
    6. Mazières J, et al.
    Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018; 379: 2040–51.
    OpenUrlCrossRefPubMed
  5. 5.
    1. Balar AV,
    2. Castellano D,
    3. O’Donnell PH,
    4. Grivas P,
    5. Vuky J,
    6. Powles T, et al.
    First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017; 18: 1483–92.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Ferris RL,
    2. Blumenschein Jr G,
    3. Fayette J,
    4. Guigay J,
    5. Colevas AD,
    6. Licitra L, et al.
    Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016; 375: 1856–67.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Brahmer JR,
    2. Tykodi SS,
    3. Chow LQ,
    4. Hwu WJ,
    5. Topalian SL,
    6. Hwu P, et al.
    Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012; 366: 2455–65.
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Abolhassani AR,
    2. Schuler G,
    3. Kirchberger MC,
    4. Heinzerling L.
    C-reactive protein as an earlymarker of immune-related adverse events. J Cancer Res Clin Oncol. 2019; 145: 2625–31.
    OpenUrl
  9. 9.↵
    1. Liudahl SM,
    2. Coussens LM.
    B cells as biomarkers: predicting immune checkpoint therapy adverse events. J Clin Invest. 2018; 128: 577–9.
    OpenUrl
  10. 10.↵
    1. Bamias G,
    2. Delladetsima I,
    3. Perdiki M,
    4. Siakavellas SI,
    5. Goukos D,
    6. Papatheodoridis GV, et al.
    Immunological characteristics of colitis associated with anti-CTLA-4 antibodytherapy. Cancer Invest. 2017; 35: 443–55.
    OpenUrl
  11. 11.↵
    1. Laufberger V.
    Bulletin de la Societe de chimiebiologique. Sur la cristallisation de la ferritine. 1937; 19: 1575–82.
    OpenUrl
  12. 12.↵
    1. Addison GM,
    2. Beamish MR,
    3. Hales CN,
    4. Hodgkins M,
    5. Jacobs A,
    6. Llewellin P.
    An immunoradiometric assay for ferritin in the serum of normal subjects and patients with iron deficiency and iron overload. J Clin Pathol. 1972; 25: 326–9.
    OpenUrlAbstract/FREE Full Text
  13. 13.↵
    1. Wesselius LJ,
    2. Nelson ME,
    3. Skikne BS.
    Increasedrelease of ferritin and iron by iron-loadedalveolar macrophages in cigarettesmokers. Am J Respir Crit Care Med. 1994; 150: 690–5.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Wang W,
    2. Knovich MA,
    3. Coffman LG,
    4. Torti FM,
    5. Torti SV.
    Serumferritin: past, present and future. Biochim Biophys Acta. 2010; 1800: 760–9.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Matzner Y,
    2. Hershko C,
    3. Polliack A,
    4. Konijn AM,
    5. Izak G.
    Suppressive effect of ferritin on in vitro lymphocyte function. Br J Haematol. 1979; 42: 345–53.
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Fargion S,
    2. Fracanzani AL,
    3. Brando B,
    4. Arosio P,
    5. Levi S,
    6. Fiorelli G.
    Specific binding sites for H-ferritin on human lymphocytes: modulation during cellular proliferation and potential implication in cell growth control. Blood. 1991; 78: 1056–61.
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    1. Good MF,
    2. Powell LW,
    3. Halliday JW.
    Iron status and cellular immune competence. Blood Rev. 1998; 2: 43–9.
    OpenUrl
  18. 18.↵
    1. Weinberg JB,
    2. Hibbs Jr JB.
    Endocytosis of red blood cells or haemoglobin by activated macrophages inhibits their tumoricidal effect. Nature. 1977; 269: 245–7.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Walker Jr EM,
    2. Walker SM.
    Effects of iron overload on the immune system. Ann Clin Lab Sci. 2000; 30: 354–65.
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. Kalantar-Zadeh K,
    2. Kalantar-Zadeh K,
    3. Lee GH.
    The fascinating but deceptive ferritin: to measure it or not to measure it in chronic kidney disease? Clin J Am Soc Nephrol. 2006; Suppl 1: S9–18.
  21. 21.↵
    1. Zandman-Goddard G,
    2. Shoenfeld Y.
    Ferritin in autoimmune diseases. Autoimmun Rev. 2007; 6: 457–63.
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Ganz T,
    2. Nemeth E.
    Ironsequestration and anemia of inflammation. Semin Hematol. 2009; 46: 387–93.
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Weinberg ED,
    2. Miklossy J.
    Iron withholding: a defense against disease. J Alzheimers Dis. 2008; 13: 451–63.
    OpenUrlPubMed
  24. 24.↵
    1. Kirkali Z,
    2. Güzelsoy M,
    3. Mungan MU,
    4. Kirkali G,
    5. Yörükoglu K.
    Serum ferritin as a clinical marker for renal cell carcinoma: influence of tumor size and volume. Urol Int. 1999; 62: 21–5.
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Hann HL,
    2. Stahlhut MW,
    3. Millman I.
    Human ferritin present in the sera of nude mice transplanted with human neuroblastoma or hepatocellular carcinoma. Cancer Res. 1984; 44: 3898–901.
    OpenUrlAbstract/FREE Full Text
  26. 26.↵
    1. Liu L,
    2. Wei Q,
    3. Lin Q,
    4. Fang J,
    5. Wang H,
    6. Kwok H, et al.
    Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI Insight. 2019; 4: e123158.
  27. 27.↵
    1. Ito M,
    2. Fujino M.
    Macrophage-mediated complications after stem cell transplantation. Pathol Int. 2019; 69: 679–87.
    OpenUrl
  28. 28.↵
    1. Koyama M,
    2. Mukhopadhyay P,
    3. Schuster IS,
    4. Henden AS,
    5. Hülsdünker J,
    6. Varelias A, et al.
    MHC class II antigen presentation by the intestinal epithelium initiates graft-versus-host disease and is influenced by the microbiota. Immunity. 2019; 51: 885–98.
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

Cancer Biology & Medicine: 18 (4)
Cancer Biology & Medicine
Vol. 18, Issue 4
1 Nov 2021
  • Table of Contents
  • Index by author
Print
Download PDF
Email Article

Thank you for your interest in spreading the word on Cancer Biology & Medicine.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Ferritin as a diagnostic, differential diagnostic, and prognostic marker for immune-related adverse events
(Your Name) has sent you a message from Cancer Biology & Medicine
(Your Name) thought you would like to see the Cancer Biology & Medicine web site.
Citation Tools
Ferritin as a diagnostic, differential diagnostic, and prognostic marker for immune-related adverse events
Weihong Zhang, Yuan Meng, Lin Yang, Meng Shen, Li Zhou, Runmei Li, Yang Wang, Weijiao Du, Yanjuan Xiong, Ying Han, Xinwei Zhang, Liang Liu, Xiubao Ren
Cancer Biology & Medicine Nov 2021, 18 (4) 1109-1117; DOI: 10.20892/j.issn.2095-3941.2021.0037

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Ferritin as a diagnostic, differential diagnostic, and prognostic marker for immune-related adverse events
Weihong Zhang, Yuan Meng, Lin Yang, Meng Shen, Li Zhou, Runmei Li, Yang Wang, Weijiao Du, Yanjuan Xiong, Ying Han, Xinwei Zhang, Liang Liu, Xiubao Ren
Cancer Biology & Medicine Nov 2021, 18 (4) 1109-1117; DOI: 10.20892/j.issn.2095-3941.2021.0037
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and methods
    • Results
    • Discussion
    • Conclusions
    • Grant support
    • Acknowledgements
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • References
  • PDF

Related Articles

  • No related articles found.
  • Google Scholar

Cited By...

  • No citing articles found.
  • Google Scholar

More in this TOC Section

  • Simultaneous integrated dose reduction intensity-modulated radiotherapy effectively reduces cardiac toxicity in limited-stage small cell lung cancer
  • Associations between polymorphisms in leptin and leptin receptor genes and colorectal cancer survival
  • Identification of the E2F1-RAD51AP1 axis as a key factor in MGMT-methylated GBM TMZ resistance
Show more Original Article

Similar Articles

Keywords

  • Ferritin
  • diagnosis
  • prognosis
  • irAEs
  • PD-1
  • chemotherapy

Navigate

  • Home
  • Current Issue

More Information

  • About CBM
  • About CACA
  • About TMUCIH
  • Editorial Board
  • Subscription

For Authors

  • Instructions for authors
  • Journal Policies
  • Submit a Manuscript

Journal Services

  • Email Alerts
  • Facebook
  • RSS Feeds
  • Twitter

 

© 2023 Cancer Biology & Medicine

Powered by HighWire