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Inflammatory and autoimmune predictive markers of response to anti‑PD‑1/PD‑L1 therapy in NSCLC and melanoma

  • Authors:
    • Aram A. Musaelyan
    • Sergey V. Lapin
    • Margarita A. Urtenova
    • Svetlana V. Odintsova
    • Ivan V. Chistyakov
    • Andrey M. Ulitin
    • Andrey L. Akopov
    • Sergey V. Orlov
  • View Affiliations / Copyright

    Affiliations: Laboratory for Diagnostics of Autoimmune Diseases, Center for Molecular Medicine, Pavlov First Saint Petersburg State Medical University, Saint Petersburg 197022, Russia, Department of Clinical Oncology, Pavlov First Saint Petersburg State Medical University, Saint Petersburg 197022, Russia, Department of Thoracic Surgery, Pavlov First Saint Petersburg State Medical University, Saint Petersburg 197022, Russia
    Copyright: © Musaelyan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 557
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    Published online on: July 5, 2022
       https://doi.org/10.3892/etm.2022.11495
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Abstract

Immune checkpoint inhibitors (ICI) are a standard in cancer therapy, but few patients respond to the treatment. The aim of the present study was the determination of immunological markers for monitoring response to ICI. The present study included 74 patients receiving ICI in subsequent [group 1; non‑small cell lung cancer (NSCLC)] and first‑line setting (group 2; melanoma) and 30 patients with NSCLC receiving first‑line chemotherapy. In groups 1 and 2 β‑2 microglobulin (B2‑MG), neopterin (NPT), IL‑6, IL‑18, HLA‑DRB1 and autoantibodies were assessed after two months of ICI, and before the start of next administration in group 3. In group 1 low level of B2‑MG (P<0.0001), NPT (P<0.0001), IL‑6 (P<0.0001), IL‑18 (P=0.0003), HLA‑DRB1*03 (P=0.016) and anti‑TPO antibodies (P=0.016) were associated with response >six months. In group 2 high level of B2‑MG (P=0.0001), NPT (P=0.0016), IL‑6 (P=0.013) and IL‑18 (P=0.032) were associated with early disease progression (<six months). Univariate analysis demonstrated that immune‑related adverse events were predictive marker of prolonged progression‑free survival (PFS) in group 1 (P=0.038) and 2 (P=0.020). Neutrophil‑lymphocyte ratio ≥5 before immunotherapy was correlated with shorter PFS in melanoma in multivariate analysis (P=0.007). B2‑MG ≥2.5 mg/ml (P=0.006) and NPT ≥12 nmol/l (P=0.027) were predictors of shorter PFS in group 1. B2‑MG ≥2.5 mg/ml was predictor of shorter PFS (P=0.008) in group 2. In group 1 levels of B2‑MG, NPT, IL‑6 and IL‑18 were higher than in group 3. In summary, immunological markers are promising predictive markers for immunotherapy; however, it requires further prospective studies.
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1 

Li S, Zhang C, Pang G and Wang P: Emerging blood-based biomarkers for predicting response to checkpoint immunotherapy in non-small-cell lung cancer. Front Immunol. 11(603157)2020.PubMed/NCBI View Article : Google Scholar

2 

Ribas A and Wolchok JD: Cancer immunotherapy using checkpoint blockade. Science. 359:1350–1355. 2018.PubMed/NCBI View Article : Google Scholar

3 

Möller M, Turzer S, Schütte W, Seliger B and Riemann D: Blood immune cell biomarkers in patient with lung cancer undergoing treatment with checkpoint blockade. J Immunother. 43:57–66. 2020.PubMed/NCBI View Article : Google Scholar

4 

Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al: Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 375:1823–1833. 2016.PubMed/NCBI View Article : Google Scholar

5 

Davis AA and Patel VG: The role of PD-L1 expression as a predictive biomarker: An analysis of all US food and drug administration (FDA) approvals of immune checkpoint inhibi. J Immunother Cancer. 7(278)2019.PubMed/NCBI View Article : Google Scholar

6 

Marcus L, Lemery SJ, Keegan P and Pazdur R: FDA approval summary: Pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin Cancer Res. 25:3753–3758. 2019.PubMed/NCBI View Article : Google Scholar

7 

Prasad V and Addeo A: The FDA approval of pembrolizumab for patients with TMB >10 mut/Mb: Was it a wise decision? No. Ann Oncol. 31:1112–1114. 2020.PubMed/NCBI View Article : Google Scholar

8 

Bai R, Lv Z, Xu D and Cui J: Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors. Biomark Res. 8(34)2020.PubMed/NCBI View Article : Google Scholar

9 

Suh KJ, Kim SH, Kim YJ, Kim M, Keam B, Kim TM, Kim DW, Heo DS and Lee JS: Post-treatment neutrophil-to-lymphocyte ratio at week 6 is prognostic in patients with advanced non-small cell lung cancers treated with anti-PD-1 antibody. Cancer Immunol Immunother. 67:459–470. 2018.PubMed/NCBI View Article : Google Scholar

10 

Keegan A, Ricciuti B, Garden P, Cohen L, Nishihara R, Adeni A, Paweletz C, Supplee J, Jänne PA, Severgnini M, et al: Plasma IL-6 changes correlate to PD-1 inhibitor responses in NSCLC. J Immunother Cancer. 8(e000678)2020.PubMed/NCBI View Article : Google Scholar

11 

Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, Meyer L, Gress DM, Byrd DR and Winchester DP: The eighth edition AJCC cancer staging manual: Continuing to build a bridge from a population-based to a more ‘personalized’ approach to cancer staging. CA Cancer J Clin. 67:93–99. 2017.PubMed/NCBI View Article : Google Scholar

12 

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009.PubMed/NCBI View Article : Google Scholar

13 

Sun JY and Lu XJ: Cancer immunotherapy: Current applications and challenges. Cancer Lett. 480:1–3. 2020.PubMed/NCBI View Article : Google Scholar

14 

Hussaini S, Chehade R, Boldt RG, Raphael J, Blanchette P, Maleki Vareki S and Fernandes R: Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors-a systematic review and meta-analysis. Cancer Treat Rev. 92(102134)2021.PubMed/NCBI View Article : Google Scholar

15 

Music M, Iafolla M, Soosaipillai A, Batruch I, Prassas I, Pintilie M, Hansen AR, Bedard PL, Lheureux S, Spreafico A, et al: Predicting response and toxicity to PD-1 inhibition using serum autoantibodies identified from immuno-mass spectrometry. F1000Res. 9(337)2020.PubMed/NCBI View Article : Google Scholar

16 

Scally SW, Petersen J, Law SC, Dudek NL, Nel HJ, Loh KL, Wijeyewickrema LC, Eckle SB, van Heemst J, Pike RN, et al: A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med. 210:2569–2582. 2013.PubMed/NCBI View Article : Google Scholar

17 

Kapustin S, Lyshchov A, Alexandrova J, Imyanitov E and Blinov M: HLA class II molecular polymorphisms in healthy Slavic individuals from North-Western Russia. Tissue Antigens. 54:517–520. 1999.PubMed/NCBI View Article : Google Scholar

18 

Lalani AA, Xie W, Martini DJ, Steinharter JA, Norton CK, Krajewski KM, Duquette A, Bossé D, Bellmunt J, Van Allen EM, et al: Change in neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma. J Immunother Cancer. 6(5)2018.PubMed/NCBI View Article : Google Scholar

19 

Li Y, Zhang Z, Hu Y, Yan X, Song Q, Wang G, Chen R, Jiao S and Wang J: Pretreatment neutrophil-to-lymphocyte ratio (NLR) may predict the outcomes of advanced non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). Front Oncol. 10(654)2020.PubMed/NCBI View Article : Google Scholar

20 

Jin J, Yang L, Liu D and Li W: Association of the neutrophil to lymphocyte ratio and clinical outcomes in patients with lung cancer receiving immunotherapy: A meta-analysis. BMJ Open. 10(e035031)2020.PubMed/NCBI View Article : Google Scholar

21 

Li L, Dong M and Wang XG: The implication and significance of beta 2 microglobulin: A conservative multifunctional regulator. Chin Med J (Engl). 129:448–455. 2016.PubMed/NCBI View Article : Google Scholar

22 

Rossi D, Fangazio M, De Paoli L, Puma A, Riccomagno P, Pinto V, Zigrossi P, Ramponi A, Monga G and Gaidano G: Beta-2-microglobulin is an independent predictor of progression in asymptomatic multiple myeloma. Cancer. 116:2188–2200. 2010.PubMed/NCBI View Article : Google Scholar

23 

Xie J, Wang Y, Freeman ME III, Barlogie B and Yi Q: Beta 2-microglobulin as a negative regulator of the immune system: High concentrations of the protein inhibit in vitro generation of functional dendritic cells. Blood. 101:4005–4012. 2003.PubMed/NCBI View Article : Google Scholar

24 

Volgger BM, Windbichler GH, Zeimet AG, Graf AH, Bogner G, Angleitner-Boubenizek L, Rohde M, Denison U, Sliutz G, Fuith LC, et al: Long-term significance of urinary neopterin in ovarian cancer: A study by the Austrian association for gynecologic oncology (AGO). Ann Oncol. 27:1740–1746. 2016.PubMed/NCBI View Article : Google Scholar

25 

Melichar B, Spisarová M, Bartoušková M, Krčmová LK, Javorská L and Študentová H: Neopterin as a biomarker of immune response in cancer patients. Ann Transl Med. 5(280)2017.PubMed/NCBI View Article : Google Scholar

26 

Liu C, Yang L, Xu H, Zheng S, Wang Z, Wang S, Yang Y, Zhang S, Feng X, Sun N and Wang Y: Systematic analysis of IL-6 as a predictive biomarker and desensitizer of immunotherapy responses in patients with non-small cell lung cancer. BMC Med. 20(187)2022.PubMed/NCBI View Article : Google Scholar

27 

Laino AS, Woods D, Vassallo M, Qian X, Tang H, Wind-Rotolo M and Weber J: Serum interleukin-6 and C-reactive protein are associated with survival in melanoma patients receiving immune checkpoint inhibition. J Immunother Cancer. 8(e000842)2020.PubMed/NCBI View Article : Google Scholar

28 

Fabbi M, Carbotti G and Ferrini S: Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP. J Leukoc Biol. 97:665–675. 2015.PubMed/NCBI View Article : Google Scholar

29 

Wang Y, Chen H, Zhang T, Yang X, Zhong J, Wang Y, Chi Y, Wu M, An T, Li J, et al: Plasma cytokines interleukin-18 and C-X-C motif chemokine ligand 10 are indicative of the anti-programmed cell death protein-1 treatment response in lung cancer patients. Ann Transl Med. 9(33)2021.PubMed/NCBI View Article : Google Scholar

30 

Terme M, Ullrich E, Aymeric L, Meinhardt K, Desbois M, Delahaye N, Viaud S, Ryffel B, Yagita H, Kaplanski G, et al: IL-18 induces PD-1-dependent immunosuppression in cancer. Cancer Res. 71:5393–5399. 2011.PubMed/NCBI View Article : Google Scholar

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Copy and paste a formatted citation
Spandidos Publications style
Musaelyan AA, Lapin SV, Urtenova MA, Odintsova SV, Chistyakov IV, Ulitin AM, Akopov AL and Orlov SV: Inflammatory and autoimmune predictive markers of response to anti‑PD‑1/PD‑L1 therapy in NSCLC and melanoma. Exp Ther Med 24: 557, 2022.
APA
Musaelyan, A.A., Lapin, S.V., Urtenova, M.A., Odintsova, S.V., Chistyakov, I.V., Ulitin, A.M. ... Orlov, S.V. (2022). Inflammatory and autoimmune predictive markers of response to anti‑PD‑1/PD‑L1 therapy in NSCLC and melanoma. Experimental and Therapeutic Medicine, 24, 557. https://doi.org/10.3892/etm.2022.11495
MLA
Musaelyan, A. A., Lapin, S. V., Urtenova, M. A., Odintsova, S. V., Chistyakov, I. V., Ulitin, A. M., Akopov, A. L., Orlov, S. V."Inflammatory and autoimmune predictive markers of response to anti‑PD‑1/PD‑L1 therapy in NSCLC and melanoma". Experimental and Therapeutic Medicine 24.3 (2022): 557.
Chicago
Musaelyan, A. A., Lapin, S. V., Urtenova, M. A., Odintsova, S. V., Chistyakov, I. V., Ulitin, A. M., Akopov, A. L., Orlov, S. V."Inflammatory and autoimmune predictive markers of response to anti‑PD‑1/PD‑L1 therapy in NSCLC and melanoma". Experimental and Therapeutic Medicine 24, no. 3 (2022): 557. https://doi.org/10.3892/etm.2022.11495
Copy and paste a formatted citation
x
Spandidos Publications style
Musaelyan AA, Lapin SV, Urtenova MA, Odintsova SV, Chistyakov IV, Ulitin AM, Akopov AL and Orlov SV: Inflammatory and autoimmune predictive markers of response to anti‑PD‑1/PD‑L1 therapy in NSCLC and melanoma. Exp Ther Med 24: 557, 2022.
APA
Musaelyan, A.A., Lapin, S.V., Urtenova, M.A., Odintsova, S.V., Chistyakov, I.V., Ulitin, A.M. ... Orlov, S.V. (2022). Inflammatory and autoimmune predictive markers of response to anti‑PD‑1/PD‑L1 therapy in NSCLC and melanoma. Experimental and Therapeutic Medicine, 24, 557. https://doi.org/10.3892/etm.2022.11495
MLA
Musaelyan, A. A., Lapin, S. V., Urtenova, M. A., Odintsova, S. V., Chistyakov, I. V., Ulitin, A. M., Akopov, A. L., Orlov, S. V."Inflammatory and autoimmune predictive markers of response to anti‑PD‑1/PD‑L1 therapy in NSCLC and melanoma". Experimental and Therapeutic Medicine 24.3 (2022): 557.
Chicago
Musaelyan, A. A., Lapin, S. V., Urtenova, M. A., Odintsova, S. V., Chistyakov, I. V., Ulitin, A. M., Akopov, A. L., Orlov, S. V."Inflammatory and autoimmune predictive markers of response to anti‑PD‑1/PD‑L1 therapy in NSCLC and melanoma". Experimental and Therapeutic Medicine 24, no. 3 (2022): 557. https://doi.org/10.3892/etm.2022.11495
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