Tumor-infiltrating CD8+ lymphocytes predict different clinical outcomes in organ- and non-organ-confined urothelial carcinoma of the bladder following radical cystectomy

Shiqiang Zhang, Jun Wang, Xinyu Zhang, Fangjian Zhou, Shiqiang Zhang, Jun Wang, Xinyu Zhang, Fangjian Zhou

Abstract

Tumor-infiltrating lymphocytes (TILs) are associated with better clinical outcomes in many tumors. TILs represent a cell-mediated immune response against the carcinoma. CD8+ TILs are a crucial component of cell-mediated immunity. The significance of CD8+ TILs has not been reported respectively in organ- and non-organ-confined urothelial carcinoma (UC) of the bladder. We explored the prognostic value of CD8+ TILs in the two groups. The presence of CD8+ TILs was assessed by immunohistochemical staining of whole tissue sections from 75 organ and 51 non-organ-confined disease patients with long-term follow-up, and its correlation with clinicopathological features and overall survival (OS) was determined. The CD8+ TIL immunohistochemical staining score was 0 (<1%), 1 (≥1%), 2 (≥5%), or 3 (≥10%) based on the percentage of positively stained cells out of total cells. A patient was considered CD8 negative if the score was 0. There were no associations between CD8+ TILs and age, sex, nuclear grade, and adjuvant or neoadjuvant chemotherapy in organ- and non-organ-confined disease. The presence of CD8+ TILs was seen more frequently in pTa-1 than pT2 stage (p = 0.033) in organ-confined disease. No associations between CD8+ TILs and pT stage, pN stage were found in non-organ-confined disease. CD8+ TILs were associated with better OS (log-rank test, P = 0.036) in non-organ-confined disease, but with poorer OS (log-rank test, P = 0.040) in organ-confined disease by the Kaplan-Meier method. In multivariate analysis, CD8+ TILs were an independent favorable prognostic factor in non-organ-confined disease, but were an independent unfavorable prognostic factor in organ-confined disease. These results suggest that CD8+ TILs have clinically significant anti-tumor activity in non-organ-confined disease, but may have pro-tumor activity in organ-confined disease. Therefore, we should be cautious if CD8+ TILs are aimed to be exploited in the treatment of bladder cancer.

Keywords: CD8+ TILs; Non-organ-confined disease; Organ-confined disease; Urothelial carcinoma of the bladder.

Conflict of interest statement

The authors declare there are no competing interests.

Figures

Figure 1. Representative examples of CD8+ TILs…
Figure 1. Representative examples of CD8+ TILs immunostaining.
CD8+ TILs are distributed mainly at the interface of the tumor and tumor-adjacent stroma. (A), (B), (C) and (D) (×100 magnification) are representative images of scores of 0, 1, 2, and 3, respectively.
Figure 2. Kaplan–Meier survival curves with log-rank…
Figure 2. Kaplan–Meier survival curves with log-rank testing.
(A) All UC of the bladder (CD8+, 90; CD8−, 36). (B) Non–organ-confined UC of the bladder (CD8+, 35; CD8−, 16). (C) Organ-confined UC of the bladder (CD8+, 55; CD8−, 20).

References

    1. Boorjian SA, Sheinin Y, Crispen PL, Farmer SA, Lohse CM, Kuntz SM, Leibovich BC, Kwon ED, Frank I. T-cell coregulatory molecule expression in urothelial cell carcinoma: clinicopathologic correlations and association with survival. Clinical Cancer Research. 2008;14:4800–4808. doi: 10.1158/1078-0432.CCR-08-0731.
    1. Cancer Genome Atlas Research Network Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507:315–322. doi: 10.1038/nature12965.
    1. Chen L. From the guest editor: tumor site immune modulation therapy. Cancer Journal. 2014;20:254–255. doi: 10.1097/PPO.0000000000000062.
    1. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nature Reviews Immunology. 2013;13:227–242. doi: 10.1038/nri3405.
    1. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10. doi: 10.1016/j.immuni.2013.07.012.
    1. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. A Cancer Journal for Clinicians. 2016;66:115–132. doi: 10.3322/caac.21338.
    1. Faraj SF, Munari E, Guner G, Taube J, Anders R, Hicks J, Meeker A, Schoenberg M, Bivalacqua T, Drake C, Netto GJ. Assessment of tumoral PD-L1 expression and intratumoral CD8+ T cells in urothelial carcinoma. Urology. 2015;85:701–703. doi: 10.1016/j.urology.2014.10.020.
    1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer. 2015;136:E359–E386. doi: 10.1002/ijc.29210.
    1. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–1964. doi: 10.1126/science.1129139.
    1. Hwang WT, Adams SF, Tahirovic E, Hagemann IS, Coukos G. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecologic Oncology. 2012;124:192–198. doi: 10.1016/j.ygyno.2011.09.039.
    1. Kaufman DS, Shipley WU, Feldman AS. Bladder cancer. Lancet. 2009;374:239–249. doi: 10.1016/S0140-6736(09)60491-8.
    1. Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, Allavena P, Torri V, Repici A, Santoro A, Mantovani A, Roncalli M, Malesci A. CD3+ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study. Lancet Oncology. 2009;10:877–884. doi: 10.1016/S1470-2045(09)70186-X.
    1. Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, Ellis IO, Green AR. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. Journal of Clinical Oncology. 2011;29:1949–1955. doi: 10.1200/JCO.2010.30.5037.
    1. Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. Journal of Urology. 1976;116:180–183. doi: 10.1016/S0022-5347(17)58737-6.
    1. Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J. Effector memory T cells, early metastasis, and survival in colorectal cancer. New England Journal of Medicine. 2005;353:2654–2666. doi: 10.1056/NEJMoa051424.
    1. Powles T, O’Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, Lee JL, Ong M, Sridhar SS, Vogelzang NJ, Fishman MN, Zhang J, Srinivas S, Parikh J, Antal J, Jin X, Gupta AK, Ben Y, Hahn NM. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncology. 2017;3:e172411. doi: 10.1001/jamaoncol.2017.2411.
    1. Sanmamed MF, Chen L. Inducible expression of B7-H1 (PD-L1) and its selective role in tumor site immune modulation. Cancer Journal. 2014;20:256–261. doi: 10.1097/PPO.0000000000000061.
    1. Sharma P, Shen Y, Wen S, Yamada S, Jungbluth AA, Gnjatic S, Bajorin DF, Reuter VE, Herr H, Old LJ, Sato E. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proceedings of the National Academy of Sciences of the United States of America. 2007;104:3967–3972. doi: 10.1073/pnas.0611618104.
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. A Cancer Journal for Clinicians. 2017;67:7–30. doi: 10.3322/caac.21387.
    1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. A Cancer Journal for Clinicians. 2015;65:87–108. doi: 10.3322/caac.21262.
    1. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568–571. doi: 10.1038/nature13954.
    1. Wang W, Kryczek I, Dostal L, Lin H, Tan L, Zhao L, Lu F, Wei S, Maj T, Peng D, He G, Vatan L, Szeliga W, Kuick R, Kotarski J, Tarkowski R, Dou Y, Rattan R, Munkarah A, Liu JR, Zou W. Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell. 2016;165:1092–1105. doi: 10.1016/j.cell.2016.04.009.
    1. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. New England Journal of Medicine. 2003;348:203–213. doi: 10.1056/NEJMoa020177.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren