Serum CCL27 predicts the response to Bacillus Calmette-Guerin immunotherapy in non-muscle-invasive bladder cancer

ABSTRACT

The prediction of the response to Bacillus Calmette-Guerin (BCG) can help identify non-muscle-invasive bladder cancer (NMIBC) patients that may be better served with alternative therapy. Several cytokine profiles present promising results, but they are difficult to use in clinical practice. In this prospective, longitudinal study, we tried to identify reliable serum cytokines/chemokines to predict the response to BCG using samples collected before and during BCG induction therapy. We used the Bio-plex multiplex assays to identify potential BCG failure-related serum cytokines/chemokines in the discovery set (n = 13). After screening, we identified CCL27 as the top candidate biomarker for predicting the response to BCG (P = .003). In the validation set, we found that the AUC of the baseline CCL27 was 0.730 (95% CI 0.515–0.945, P = .040) along with 67% sensitivity, 78% specificity. The changes from baseline to last timepoint can also distinguish BCG responders from non-responders (AUC: 0.726, 95% CI 0.474–0.979, P = .044). Moreover, the combination score of serum CCL27 (CS_CCL27), based on the baseline and changes of CCL27, could further improve the predictive accuracy with an AUC of 0.897 (95% CI 0.790–1.000, P < .001). The correlations between CCL27 and local/systemic immunologic parameters were further analyzed. The level of serum CCL27 was strongly correlated with regulatory T cells (Tregs) in the tumor microenvironment (P = .002), indicating that CCL27 may promote the recruitment of Tregs into the tumor microenvironment. Our results show that serum CCL27 may represent a practical and reliable marker for the prediction of the response to BCG in NMIBC.

KEYWORDS:

• CCL27
• Bacillus Calmette-Guerin (BCG)
• non-muscle-invasive bladder cancer (NMIBC)
• regulatory T cells (Tregs)
• response

Author contribution

Wenlong Zhong and Bo Wang designed the experiment, analyzed the data and wrote the manuscript; Hao Yu, Meihua Yang and Weibin Hou performed the cytokines and chemokines analysis; Hao Yu and Kun Xia collected the samples and clinic data; Junyu Chen, Meng Yang and Xiaofei Wang performed the immunohistochemical staining and evaluate the immunohistochemical makers of tissue sections, Lin T modified and revised the manuscript; Huang J supervised in the design of the study and finalized the manuscript.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 81772719, 81825016, 81902586, 81961128027); Fundamental Research Funds for the Central Universities (19ykpy116, 19ykpy117); Guangdong Science and Technology Development Fund (2017B020227007); Guangdong Basic and Applied Basic Research Foundation (2020A1515011312); Pearl River Nova Program of Guangzhou (201806010024); China Postdoctoral Science Foundation (No. 2018M640862); Elite Young Scholars Development Program of Sun Yat-Sen Memorial Hospital to Bo Wang; Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun-Yat-Sen University (Grant No. KLB09001); Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology (Grant No. 013-163).