High Expression of Immune Checkpoint Molecules in Different Types of Thyroid Cancer
-
Mahdi Sajedi Shacker
,
Amir Reza Dehghanian
,
Razie Kiani
,
Mohammad Reza Haghshenas
,
Nasrollah Erfani
Abstract
This study aimed to investigate the expression of programmed cell death protein-1 (PD-1) and its ligand (PD-L1) immune checkpoint molecules in thyroid carcinomas and determine their association with the clinicopathological characteristics of patients.
Thyroid tissue specimens from 100 patients diagnosed with primary thyroid carcinomas including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC) were collected. Sections were prepared from formalin-fixed paraffin-embedded samples, and PD-1 and PD-L1 expressions were examined using immunohistochemistry.
PD-1 was detected in tumor-infiltrating lymphocytes (TILs) in 88% of the patients and tumor cells in 28% of the patients with 10% in PTC, 5% in FTC, 5% in MTC, and 8% in ATC). PD-L1 was found in tumor cells and TILs in 30% and 79% of the patients, respectively. Moreover, a significant difference was observed in PD-1 and PD-L1 expression between tumor cells and TILs across different tumor types. However, their expression in tumor cells and TILs was significantly higher in ATC compared to other tumor types. Additionally, the expression of PD-1 and PD-L1 was significantly associated with an advanced stage, higher tumor size, tumor necrosis, and mitosis. A significant positive correlation was also observed between the expression of PD-1 and PD-L1 in tumor cells and TILs.
The higher expression of PD-1 and PD-L1 may contribute to tumor progression. Therefore, combinational immunotherapy by these immune checkpoint inhibitors might be a promising strategy for clinical improvement in patients with thyroid cancer, especially those with ATC.
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8. Marcucci F, Rumio C, Corti A. Tumor cell-associated immune checkpoint molecules - Drivers of malignancy and stemness. Biochimica et biophysica acta Reviews on cancer. 2017;1868(2):571-83.
9. Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. The Journal of clinical investigation. 2015;125(9):3384-91.
10. Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. American journal of cancer research. 2020;10(3):727-42.
11. Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations. Frontiers in oncology. 2018;8:86.
12. Niloofar N, Mehdi M, Simin A, Bahare S, Abbas G. Expression of PD-1 in Tumor Cells is Associated with Shorter Survival in Non-metastatic Intestinal-type Gastric Adenocarcinoma. Iranian Journal of Allergy, Asthma and Immunology. 2022;21(6).
13. Gulinac M, Dikov D, Velikova T, Belovezhdov V. Increased PD-L1 expression in high-grade bladder cancer with squamous cell differentiation in Bulgarian and French patients' samples. Annals of diagnostic pathology. 2020;49:151640.
14. Liu J, Li H, Sun L. Profiles of PD-1, PD-L1, PD-L2 in Gastric Cancer and Their Relation with Mutation, Immune Infiltration, and Survival. 2020;2020:2496582.
15. Matikas A, Zerdes I, Lövrot J. Prognostic Implications of PD-L1 Expression in Breast Cancer: Systematic Review and Meta-analysis of Immunohistochemistry and Pooled Analysis of Transcriptomic Data. 2019;25(18):5717-26.
16. Gerdabi S, Asadian F, Kiani R, Khademi B, Haghshenas MR, Erfani N. Simultaneous Expression of PD-1 and PD-L1 in Peripheral and Central Immune Cells and Tumor Cells in the Benign and Malignant Salivary Gland Tumors Microenvironment. Head and Neck Pathology. 2023;17(1):178-92.
17. Farahani H, Dehghanian AR, Khademolhosseini A, Haghshenas MR, Erfani N. Frequent expression of CD45RO memory T cell marker as well as low to high expression of PD-1 and PD-L1 inhibitory molecules in seminoma and dysgerminoma. Journal of reproductive immunology. 2024;161:104184.
18. Ahn S, Kim TH, Kim SW, Ki CS, Jang HW, Kim JS, et al. Comprehensive screening for PD-L1 expression in thyroid cancer. Endocrine-related cancer. 2017;24(2):97-106.
19. Chintakuntlawar AV, Rumilla KM, Smith CY, Jenkins SM, Foote RL, Kasperbauer JL, et al. Expression of PD-1 and PD-L1 in Anaplastic Thyroid Cancer Patients Treated With Multimodal Therapy: Results From a Retrospective Study. The Journal of clinical endocrinology and metabolism. 2017;102(6):1943-50.
20. Haghshenas MR, Dabbaghmanesh MH, Miri A, Ghaderi A, Erfani N. Association of PDCD1 gene markers with susceptibility to thyroid cancer. Journal of endocrinological investigation. 2017;40(5):481-6.
21. French JD. Immunotherapy for advanced thyroid cancers - rationale, current advances and future strategies. Nature reviews Endocrinology. 2020;16(11):629-41.
22. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Annals of oncology: official journal of the European Society for Medical Oncology. 2015;26(2):259-71.
23. Bai Y, Niu D, Huang X, Jia L, Kang Q, Dou F, et al. PD-L1 and PD-1 expression are correlated with distinctive clinicopathological features in papillary thyroid carcinoma. Diagnostic pathology. 2017;12(1):72.
24. Bi Y, Ren X, Bai X, Meng Y, Luo Y, Cao J, et al. PD-1/PD-L1 expressions in medullary thyroid carcinoma: Clinicopathologic and prognostic analysis of Chinese population. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2019;45(3):353-8.
25. Kleffel S, Posch C, Barthel SR, Mueller H, Schlapbach C, Guenova E, et al. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. Cell. 2015;162(6):1242-56.
26. Yao H, Wang H, Li C, Fang JY, Xu J. Cancer Cell-Intrinsic PD-1 and Implications in Combinatorial Immunotherapy. Frontiers in immunology. 2018;9:1774.
27. Wang X, Yang X. Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy. 2020;117(12):6640-50.
28. Li H, Li X, Liu S, Guo L, Zhang B, Zhang J, et al. Programmed cell death-1 (PD-1) checkpoint blockade in combination with a mammalian target of rapamycin inhibitor restrains hepatocellular carcinoma growth induced by hepatoma cell-intrinsic PD-1. Hepatology (Baltimore, Md). 2017;66(6):1920-33.
29. Rosenbaum MW, Gigliotti BJ, Pai SI, Parangi S, Wachtel H, Mino-Kenudson M, et al. PD-L1 and IDO1 Are Expressed in Poorly Differentiated Thyroid Carcinoma. Endocrine pathology. 2018;29(1):59-67.
30. Shakerin P, Sedighi Moghadam B, Baghaei K, Safaei Naraghi Z, Kamyab Hesari K, Asadzadeh Aghdaei H, et al. Increasing the expression of programmed death ligand 2 (PD-L2) but not 4-1BB ligand in colorectal cancer cells. 2020;47(8):5689-97.
31. Wan B, Deng P, Dai W, Wang P, Dong Z, Yang C, et al. Association between programmed cell death ligand 1 expression and thyroid cancer: A meta-analysis. Medicine. 2021;100(14):e25315.
32. Girolami I, Pantanowitz L, Mete O, Brunelli M, Marletta S, Colato C, et al. Programmed Death-Ligand 1 (PD-L1) Is a Potential Biomarker of Disease-Free Survival in Papillary Thyroid Carcinoma: a Systematic Review and Meta-Analysis of PD-L1 Immunoexpression in Follicular Epithelial Derived Thyroid Carcinoma. 2020;31(3):291-300.
33. Uhercik M, Sanders AJ, Owen S, Davies EL, Sharma AK, Jiang WG, et al. Clinical Significance of PD1 and PDL1 in Human Breast Cancer. Anticancer research. 2017;37(8):4249-54.
34. Ma K, Wei X, Dong D, Wu Y, Geng Q, Li E. PD-L1 and PD-1 expression correlate with prognosis in extrahepatic cholangiocarcinoma. Oncology letters. 2017;14(1):250-6.
35. Capdevila J, Wirth LJ, Ernst T, Ponce Aix S, Lin CC, Ramlau R, et al. PD-1 Blockade in Anaplastic Thyroid Carcinoma. 2020;38(23):2620-7.
36. Yang SR, Tsai MH, Hung CJ, Peng SL, Chiu NT, Huang YH, et al. Anaplastic Thyroid Cancer Successfully Treated With Radiation and Immunotherapy: A Case Report. AACE clinical case reports. 2021;7(5):299-302.
37. Yin H, Tang Y, Guo Y, Wen S. Immune Microenvironment of Thyroid Cancer. Journal of Cancer. 2020;11(16):4884-96.
38. Shi X, Li CW, Tan LC, Wen SS, Liao T, Zhang Y, et al. Immune Co-inhibitory Receptors PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT in Medullary Thyroid Cancers: A Large Cohort Study. The Journal of clinical endocrinology and metabolism. 2021;106(1):120-32.
26. Morquette B, Juźwik CA, Drake SS, Charabati M, Zhang Y, Lécuyer M-A, et al. MicroRNA-223 protects neurons from degeneration in experimental autoimmune encephalomyelitis. Brain. 2019;142(10):2979-95.
2. Cabanillas ME, McFadden DG, Durante C. Thyroid cancer. Lancet (London, England). 2016;388(10061):2783-95.
3. Katoh H, Yamashita K, Enomoto T, Watanabe M, editors. Classification and General Considerations of Thyroid Cancer2015.
4. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid : official journal of the American Thyroid Association. 2016;26(1):1-133.
5. Laha D, Nilubol N, Boufraqech M. New Therapies for Advanced Thyroid Cancer. Frontiers in endocrinology. 2020;11:82.
6. Naoum GE, Morkos M, Kim B, Arafat W. Novel targeted therapies and immunotherapy for advanced thyroid cancers. Molecular cancer. 2018;17(1):51.
7. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature reviews Cancer. 2012;12(4):252-64.
8. Marcucci F, Rumio C, Corti A. Tumor cell-associated immune checkpoint molecules - Drivers of malignancy and stemness. Biochimica et biophysica acta Reviews on cancer. 2017;1868(2):571-83.
9. Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. The Journal of clinical investigation. 2015;125(9):3384-91.
10. Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. American journal of cancer research. 2020;10(3):727-42.
11. Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations. Frontiers in oncology. 2018;8:86.
12. Niloofar N, Mehdi M, Simin A, Bahare S, Abbas G. Expression of PD-1 in Tumor Cells is Associated with Shorter Survival in Non-metastatic Intestinal-type Gastric Adenocarcinoma. Iranian Journal of Allergy, Asthma and Immunology. 2022;21(6).
13. Gulinac M, Dikov D, Velikova T, Belovezhdov V. Increased PD-L1 expression in high-grade bladder cancer with squamous cell differentiation in Bulgarian and French patients' samples. Annals of diagnostic pathology. 2020;49:151640.
14. Liu J, Li H, Sun L. Profiles of PD-1, PD-L1, PD-L2 in Gastric Cancer and Their Relation with Mutation, Immune Infiltration, and Survival. 2020;2020:2496582.
15. Matikas A, Zerdes I, Lövrot J. Prognostic Implications of PD-L1 Expression in Breast Cancer: Systematic Review and Meta-analysis of Immunohistochemistry and Pooled Analysis of Transcriptomic Data. 2019;25(18):5717-26.
16. Gerdabi S, Asadian F, Kiani R, Khademi B, Haghshenas MR, Erfani N. Simultaneous Expression of PD-1 and PD-L1 in Peripheral and Central Immune Cells and Tumor Cells in the Benign and Malignant Salivary Gland Tumors Microenvironment. Head and Neck Pathology. 2023;17(1):178-92.
17. Farahani H, Dehghanian AR, Khademolhosseini A, Haghshenas MR, Erfani N. Frequent expression of CD45RO memory T cell marker as well as low to high expression of PD-1 and PD-L1 inhibitory molecules in seminoma and dysgerminoma. Journal of reproductive immunology. 2024;161:104184.
18. Ahn S, Kim TH, Kim SW, Ki CS, Jang HW, Kim JS, et al. Comprehensive screening for PD-L1 expression in thyroid cancer. Endocrine-related cancer. 2017;24(2):97-106.
19. Chintakuntlawar AV, Rumilla KM, Smith CY, Jenkins SM, Foote RL, Kasperbauer JL, et al. Expression of PD-1 and PD-L1 in Anaplastic Thyroid Cancer Patients Treated With Multimodal Therapy: Results From a Retrospective Study. The Journal of clinical endocrinology and metabolism. 2017;102(6):1943-50.
20. Haghshenas MR, Dabbaghmanesh MH, Miri A, Ghaderi A, Erfani N. Association of PDCD1 gene markers with susceptibility to thyroid cancer. Journal of endocrinological investigation. 2017;40(5):481-6.
21. French JD. Immunotherapy for advanced thyroid cancers - rationale, current advances and future strategies. Nature reviews Endocrinology. 2020;16(11):629-41.
22. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Annals of oncology: official journal of the European Society for Medical Oncology. 2015;26(2):259-71.
23. Bai Y, Niu D, Huang X, Jia L, Kang Q, Dou F, et al. PD-L1 and PD-1 expression are correlated with distinctive clinicopathological features in papillary thyroid carcinoma. Diagnostic pathology. 2017;12(1):72.
24. Bi Y, Ren X, Bai X, Meng Y, Luo Y, Cao J, et al. PD-1/PD-L1 expressions in medullary thyroid carcinoma: Clinicopathologic and prognostic analysis of Chinese population. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2019;45(3):353-8.
25. Kleffel S, Posch C, Barthel SR, Mueller H, Schlapbach C, Guenova E, et al. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. Cell. 2015;162(6):1242-56.
26. Yao H, Wang H, Li C, Fang JY, Xu J. Cancer Cell-Intrinsic PD-1 and Implications in Combinatorial Immunotherapy. Frontiers in immunology. 2018;9:1774.
27. Wang X, Yang X. Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy. 2020;117(12):6640-50.
28. Li H, Li X, Liu S, Guo L, Zhang B, Zhang J, et al. Programmed cell death-1 (PD-1) checkpoint blockade in combination with a mammalian target of rapamycin inhibitor restrains hepatocellular carcinoma growth induced by hepatoma cell-intrinsic PD-1. Hepatology (Baltimore, Md). 2017;66(6):1920-33.
29. Rosenbaum MW, Gigliotti BJ, Pai SI, Parangi S, Wachtel H, Mino-Kenudson M, et al. PD-L1 and IDO1 Are Expressed in Poorly Differentiated Thyroid Carcinoma. Endocrine pathology. 2018;29(1):59-67.
30. Shakerin P, Sedighi Moghadam B, Baghaei K, Safaei Naraghi Z, Kamyab Hesari K, Asadzadeh Aghdaei H, et al. Increasing the expression of programmed death ligand 2 (PD-L2) but not 4-1BB ligand in colorectal cancer cells. 2020;47(8):5689-97.
31. Wan B, Deng P, Dai W, Wang P, Dong Z, Yang C, et al. Association between programmed cell death ligand 1 expression and thyroid cancer: A meta-analysis. Medicine. 2021;100(14):e25315.
32. Girolami I, Pantanowitz L, Mete O, Brunelli M, Marletta S, Colato C, et al. Programmed Death-Ligand 1 (PD-L1) Is a Potential Biomarker of Disease-Free Survival in Papillary Thyroid Carcinoma: a Systematic Review and Meta-Analysis of PD-L1 Immunoexpression in Follicular Epithelial Derived Thyroid Carcinoma. 2020;31(3):291-300.
33. Uhercik M, Sanders AJ, Owen S, Davies EL, Sharma AK, Jiang WG, et al. Clinical Significance of PD1 and PDL1 in Human Breast Cancer. Anticancer research. 2017;37(8):4249-54.
34. Ma K, Wei X, Dong D, Wu Y, Geng Q, Li E. PD-L1 and PD-1 expression correlate with prognosis in extrahepatic cholangiocarcinoma. Oncology letters. 2017;14(1):250-6.
35. Capdevila J, Wirth LJ, Ernst T, Ponce Aix S, Lin CC, Ramlau R, et al. PD-1 Blockade in Anaplastic Thyroid Carcinoma. 2020;38(23):2620-7.
36. Yang SR, Tsai MH, Hung CJ, Peng SL, Chiu NT, Huang YH, et al. Anaplastic Thyroid Cancer Successfully Treated With Radiation and Immunotherapy: A Case Report. AACE clinical case reports. 2021;7(5):299-302.
37. Yin H, Tang Y, Guo Y, Wen S. Immune Microenvironment of Thyroid Cancer. Journal of Cancer. 2020;11(16):4884-96.
38. Shi X, Li CW, Tan LC, Wen SS, Liao T, Zhang Y, et al. Immune Co-inhibitory Receptors PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT in Medullary Thyroid Cancers: A Large Cohort Study. The Journal of clinical endocrinology and metabolism. 2021;106(1):120-32.
26. Morquette B, Juźwik CA, Drake SS, Charabati M, Zhang Y, Lécuyer M-A, et al. MicroRNA-223 protects neurons from degeneration in experimental autoimmune encephalomyelitis. Brain. 2019;142(10):2979-95.
| Files | ||
| Issue | Vol 23 No 5 (2024) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v23i5.16747 | |
| Keywords | ||
| Immune checkpoint Immunohistochemistry Programmed cell death 1 receptor Programmed cell death ligand Thyroid cancer | ||
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How to Cite
1.
Sajedi Shacker M, Dehghanian AR, Kiani R, Haghshenas MR, Erfani N. High Expression of Immune Checkpoint Molecules in Different Types of Thyroid Cancer. Iran J Allergy Asthma Immunol. 2024;23(5):514-525.
