Single-cell analysis identifies distinct populations of cytotoxic CD4+ T cells (CD4+ CTLs) linked to the therapeutic efficacy of immune checkpoint inhibitors in metastatic renal cell carcinoma.
Author:
Yang Xu1, Wu Jianwei1, Fan Longlong2, Chen Binghua3, Zhang Shiqiang4, Zheng Wenzhong1
Affiliation:
1. Fujian Medical University Union Hospital 2. The Eighth Affiliated Hospital, Sun Yat-sen University 3. Pingtan Branch of Fujian Medical University Union Hospital 4. The Seventh Affiliated Hospital of Sun Yat-sen University
Abstract
Abstract
Purpose
In this study, we systematically evaluated CD4+ T cell subtypes and investigated the correlation between tumor-specific cytotoxic CD4+ T cells (CD4+ CTLs) and the therapeutic efficacy in metastatic renal cell carcinoma (mRCC) patients.
Methods
The expression patterns of CD4+ T lymphocytes subtypes in RCC patients were systematically characterized using CD4+ T lymphocytes single-cell RNA sequencing, and verification via immunofluorescent staining techniques. Datasets of mRCC patients undergoing immunotherapy were analyzed to assess the synergistic role of CD4+ CTLs in predicting responses to immune checkpoint inhibitors (ICIs). The CD4+ CTLs signature score was derived from the CheckMate 009, 010, and 025 bulk RNA-seq datasets using CIBERSORTx algorithms.
Results
We found that cytotoxic CD4+ T cells accounted for a significant proportion among all CD4+ T lymphocyte sub-clusters in mRCC patients. Additionally, two distinct cytotoxic states, CD4+GZMK+ T cells with weak cytotoxic activity and CD4+GZMB+ T cells with strong cytotoxic activity, were identified in mRCC patients. Both regulatory T cells and CD4+ CTLs were derived from proliferating CD4+ T cells in mRCC tissues. Moreover, trajectory analysis showed that weak cytotoxic CD4+GZMK+ T cells differentiated from higher cytotoxic CD4+GZMB+ T cells. Higher CD4 + CTLs abundance group showed better prognosis in the CheckMate 009, 010, and 025 immunotherapy cohorts.
Conclusions
Our study suggests that intratumoral CD4+ CTLs may play a crucial role in anti-tumor immunity and could serve as a potential marker for predicting the therapeutic efficacy of immune checkpoint inhibitors in mRCC patients.
Publisher
Research Square Platform LLC
Reference43 articles.
1. H. Sung, J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, and F. Bray, CA: A Cancer Journal for Clinicians 71, 209–249 (2021) 10.3322/caac.21660 2. U. Capitanio, F. Montorsi, The Lancet. 387, 894–906 (2016). 10.1016/s0140-6736(15)00046-x 3. T.K. Choueiri, D.L. Longo, R.J. Motzer, N. Engl. J. Med. 376, 354–366 (2017). 10.1056/NEJMra1601333 4. T.K. Kim, E.N. Vandsemb, R.S. Herbst, L. Chen, Nat. Rev. Drug Discovery. 21, 529–540 (2022). 10.1038/s41573-022-00493-5 5. R.J. Motzer, B. Escudier, D.F. McDermott, S. George, H.J. Hammers, S. Srinivas, S.S. Tykodi, J.A. Sosman, G. Procopio, E.R. Plimack, D. Castellano, T.K. Choueiri, H. Gurney, F. Donskov, P. Bono, J. Wagstaff, T.C. Gauler, T. Ueda, Y. Tomita, F.A. Schutz, C. Kollmannsberger, J. Larkin, A. Ravaud, J.S. Simon, L.-A. Xu, I.M. Waxman, P. Sharma, N. Engl. J. Med. 373, 1803–1813 (2015). 10.1056/NEJMoa1510665
|
|