Predictive value of sST2 level in immune-related adverse events

doi:10.19401/j.cnki.1007-3639.2022.08.006

Abstract

Abstract:

Background and purpose: Immune checkpoint inhibitors (ICIs) have changed the landscape of cancer treatment during the last 10 years. They have significantly extended survival for patients with malignancy. However, immune-related adverse events (irAE) have been reported and attracted attention with widespread use of ICIs. Currently, there is no reliable biomarker to clinically predict the risk of irAE. This study established a risk prediction model of irAE in tumor patients receiving ICIs based on multiple biological indicators. Methods: A total of 91 patients treated in Zhongshan Hospital of Fudan University from October 2018 to December 2020 were included in the study. Patients included in the study were divided into irAE group and control group according to whether they had grade 2 or higher irAE after receiving ICIs. Biological indicators including serum soluble form of suppression of tumorigenicity-2 (sST2), prognostic nutritional index (PNI) and platelet to lymphocyte ratio (PLR) were collected before and after ICIs treatment. Logistic regression model containing these biomarkers was constructed to predict the risk of irAE. Results: A total of 13 patients in the irAE group. Baseline PNI level, baseline PLR level and post-treatment sST2 peak level showed a significant difference between the irAE group and control group (P<0.05, P<0.05 and P<0.01 respectively). Logistic regression analysis showed that lower baseline PNI level, baseline PLR level and higher post-treatment sST2 peak level were independent risk factors for irAE after ICIs treatment (odds ratio were 0.790, 0.997, and 1.013 respectively). The area under the receiver operating characteristic (ROC) curve was 0.857. Conclusion: Higher sST2 level is an independent risk factor for irAE. The logistic model consisted of sST2, PNI and PLR has a good predictive ability for the risk of irAE after ICIs treatment.

Key words: Immune checkpoint inhibitors, Immune-related adverse events, Suppression of tumorigenicity2, Prediction model

CLC Number:

R738.6

XU Yuchen, CHENG Leilei, WANG Yan, LIN Jinyi, CHEN Jiahui, CHEN Yifan, ZHOU Yuhong, LIU Tianshu, GE Junbo. Predictive value of sST2 level in immune-related adverse events[J]. China Oncology, 2022, 32(8): 712-718.

Figures/Tables 4

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References 24

[1]	RAMOS-CASALS M, BRAHMER J R, CALLAHAN M K, et al. Immune-related adverse events of checkpoint inhibitors[J]. Nat Rev Dis Primers, 2020, 6: 38. doi: 10.1038/s41572-020-0160-6
[2]	MORAD G, HELMINK B A, SHARMA P, et al. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade[J]. Cell, 2022, 185(3): 576. doi: 10.1016/j.cell.2022.01.008
[3]	GEENEN L W, BAGGEN V J M, KAULING R M, et al. The prognostic value of soluble ST2 in adults with pulmonary hypertension[J]. J Clin Med, 2019, 8(10): E1517.
[4]	ALTARA R, GHALI R, MALLAT Z, et al. Conflicting vascular and metabolic impact of the IL-33/sST2 axis[J]. Cardiovasc Res, 2018, 114(12): 1578-1594. doi: 10.1093/cvr/cvy166
[5]	GÜNTHER F, STRAUB R H, HARTUNG W, et al. Increased serum levels of soluble ST2 as a predictor of disease progression in systemic sclerosis[J]. Scand J Rheumatol, 2022, 51(4): 315-322. doi: 10.1080/03009742.2021.1929457
[6]	MECHTOUFF L, PACCALET A, CROLA DA SILVA C, et al. Prognosis value of serum soluble ST2 level in acute ischemic stroke and STEMI patients in the era of mechanical reperfusion therapy[J]. J Neurol, 2022, 269(5): 2641-2648. doi: 10.1007/s00415-021-10865-3
[7]	URBAN M H, STOJKOVIC S, DEMYANETS S, et al. Soluble ST2 and all-cause mortality in patients with chronic obstructive pulmonary disease-a 10-year cohort study[J]. J Clin Med, 2021, 11(1): 56. doi: 10.3390/jcm11010056
[8]	中国临床肿瘤学会指南工作委员会组织. 中国临床肿瘤学会(CSCO)肿瘤相关性贫血临床实践指南2021[M]. 北京: 人民卫生出版社, 2021.
	Guidelines Working Committee of Chinese Society of Clinical Oncology. Chinese Society of Clinical Oncology (CSCO) clinical practice guideline for tumor associated anemia 2021[M]. Beijing: People's Health Publishing House, 2021.
[9]	SCHNEIDER B J, NAIDOO J, SANTOMASSO B D, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update[J]. J Clin Oncol, 2021, 39(36): 4073-4126. doi: 10.1200/JCO.21.01440
[10]	MICHOT J M, BIGENWALD C, CHAMPIAT S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review[J]. Eur J Cancer, 2016, 54: 139-148. doi: 10.1016/j.ejca.2015.11.016
[11]	VILLACORTA H, MAISEL A S. Soluble ST2 testing: a promising biomarker in the management of heart failure[J]. Arq Bras Cardiol, 2016, 106(2): 145-152.
[12]	PASCUAL-FIGAL D A, MANZANO-FERNÁNDEZ S, BORONAT M, et al. Soluble ST2, high-sensitivity troponin T- and N-terminal pro-B-type natriuretic peptide: complementary role for risk stratification in acutely decompensated heart failure[J]. Eur J Heart Fail, 2011, 13(7): 718-725. doi: 10.1093/eurjhf/hfr047
[13]	ZILE M R, JHUND P S, BAICU C F, et al. Plasma biomarkers reflecting profibrotic processes in heart failure with a preserved ejection fraction: data from the prospective comparison of ARNI with ARB on management of heart failure with preserved ejection fraction study[J]. Circ Heart Fail, 2016, 9(1): e002551.
[14]	PEI C, BARBOUR M, FAIRLIE-CLARKE K J, et al. Emerging role of interleukin-33 in autoimmune diseases[J]. Immunology, 2014, 141(1): 9-17. doi: 10.1111/imm.12174
[15]	BERGIS D, KASSIS V, RADEKE H H. High plasma sST2 levels in gastric cancer and their association with metastatic disease[J]. Cancer Biomark, 2016, 16(1): 117-125. doi: 10.3233/CBM-150547
[16]	GONUGUNTA A S, VON ITZSTEIN M S, MU-MOSLEY H, et al. Humoral and cellular correlates of a novel immune-related adverse event and its treatment[J]. J Immunother Cancer, 2021, 9(12): e003585.
[17]	ZHANG J L, RAMADAN A M, GRIESENAUER B, et al. ST2 blockade reduces sST2-producing T cells while maintaining protective mST2-expressing T cells during graft-versus-host disease[J]. Sci Transl Med, 2015, 7(308): 308ra160.
[18]	FAUSTINO L D, GRIFFITH J W, RAHIMI R A, et al. Interleukin-33 activates regulatory T cells to suppress innate γδ T cell responses in the lung[J]. Nat Immunol, 2020, 21(11): 1371-1383. doi: 10.1038/s41590-020-0785-3
[19]	NGO THI PHUONG N, PALMIERI V, ADAMCZYK A, et al. IL-33 drives expansion of type 2 innate lymphoid cells and regulatory T cells and protects mice from severe, acute colitis[J]. Front Immunol, 2021, 12: 669787. doi: 10.3389/fimmu.2021.669787
[20]	EGAMI S, KAWAZOE H, HASHIMOTO H, et al. Absolute lymphocyte count predicts immune-related adverse events in patients with non-small cell lung cancer treated with nivolumab monotherapy: a multicenter retrospective study[J]. Front Oncol, 2021, 11: 618570. doi: 10.3389/fonc.2021.618570
[21]	SHIMOZAKI K, SUKAWA Y, SATO Y, et al. Analysis of risk factors for immune-related adverse events in various solid tumors using real-world data[J]. Future Oncol, 2021, 17(20): 2593-2603. doi: 10.2217/fon-2020-0861
[22]	MATSUKANE R, WATANABE H, MINAMI H, et al. Continuous monitoring of neutrophils to lymphocytes ratio for estimating the onset, severity, and subsequent prognosis of immune related adverse events[J]. Sci Rep, 2021, 11(1): 1324. doi: 10.1038/s41598-020-79397-6
[23]	LIU W H, LIU Y P, MA F, et al. Peripheral blood markers associated with immune-related adverse effects in patients who had advanced non-small cell lung cancer treated with PD-1 inhibitors[J]. Cancer Manag Res, 2021, 13: 765-771. doi: 10.2147/CMAR.S293200
[24]	EGAMI S, KAWAZOE H, HASHIMOTO H, et al. Peripheral blood biomarkers predict immune-related adverse events in non-small cell lung cancer patients treated with pembrolizumab: a multicenter retrospective study[J]. J Cancer, 2021, 12(7): 2105-2112. doi: 10.7150/jca.53242

Characteristics	irAE	Control	t value	P value
Platelet count /(10⁹·L^-1)	202.7±131.7	252.3±110.3	1.455	0.1492
B cell count /(10⁹·L^-1)	165.1±138.6	123.0±89.8	-1.370	0.175
CD4⁺/CD8⁺T cell ratio	1.8±1.1	2.0±2.9	0.174	0.862
D-dimer /(mg·L^-1)	1.3±1.4	1.8±2.4	0.611	0.543
sST2 /(ng·L^-1)	37.6±3.1	35.0±26.1	-0.194	0.848
NLR	9.1±4.6	11.3±7.0	1.093	0.277
PNI	41.6±3.3	45.8±6.4	2.310	0.023^*
PLR	422.2±339.8	614.3±289.0	0.034	0.034^*

Characteristics	irAE	Control	t/t’ value	P value
sST2 /(ng·mL^-1)	94.69±102.72	38.41±22.58	-3.927	0.000 3^*
cTnT /(μg·mL^-1)	0.13±0.27	0.01±0.01	-1.573	0.142
BNP /(pg·mL^-1)	899.4±1382.5	188.5±282.5	-1.847	0.089

Characteristics	β	Standard Error	Wald χ²	P value	OR (95% CI）
sST2/(ng·mL^-1)	0.013	0.006	4.884	0.027	1.013 (1.001-1.025)
PNI	-0.224	0.097	5.309	0.021	0.790 (0.660-0.967)
PLR	-0.003	0.002	5.195	0.023	0.997 (0.994-1.000)