The clinical significance and immune correlation of CD103+ cells in prostate cancer (PCa) remain explored.
In total, 1080 patients with PCa underwent radical prostatectomy from three cohorts were enrolled for retrospective analysis. Tumour microarrays were constructed and fresh tumour samples were analysed by flow cytometry.
High CD103+ cell infiltration correlated with reduced biochemical recurrence (BCR)-free survival in PCa. Adjuvant hormone therapy (HT) prolonged the BCR-free survival for high-risk node-negative diseases with CD103+ cell abundance. CD103+ cell infiltration correlated with less cytotoxic expression and increased infiltration of CD8+ and CD4+ T cells, M1 macrophages and mast cells in PCa. Intratumoral CD8+ T cell was the predominant source of CD103, and the CD103+ subset of CD8+ T cells was featured with high IL-10, PD-1 and CTLA-4 expression. Tumour-infiltrating CD103+ CD8+ T cells exerted anti-tumour function when treated with HT ex vivo.
CD103+ cell infiltration predicted BCR-free survival and response to adjuvant HT in PCa. CD103+ cell infiltration correlated with an enriched but immune-evasive immune landscape. The study supported a model that CD103 expression conferred negative prognostic impact and immunosuppressive function to tumour-infiltrating CD8+ T cells, while the CD103+ CD8+ T cells exhibited a powerful anti-tumour immunity with response to HT.
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All data generated that are relevant to the results presented in this article are included in this article. Other data that were not relevant for the results presented here are available from the corresponding author Dr. Jiang upon reasonable request.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA A Cancer J Clin. 2020;70:7–30.
Wilkins LJ, Tosoian JJ, Sundi D, Ross AE, Grimberg D, Klein EA, et al. Surgical management of high-risk, localized prostate cancer. Nat Rev Urol. 2020;17:679–90.
Rebello RJ, Oing C, Knudsen KE, Loeb S, Johnson DC, Reiter RE, et al. Prostate cancer. Nat Rev Dis Prim. 2021;7:9.
Mottet N, van den Bergh RCN, Briers E, Van den Broeck T, Cumberbatch MG, De Santis M, et al. EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate cancer—2020 update. Part 1: screening, diagnosis, and local treatment with curative intent. Eur Urol. 2021;79:243–62.
Tosco L, Briganti A, D’amico AV, Eastham J, Eisenberger M, Gleave M, et al. Systematic review of systemic therapies and therapeutic combinations with local treatments for high-risk localized prostate cancer. Eur Urol. 2019;75:44–60.
Zhao SG, Chang SL, Erho N, Yu M, Lehrer J, Alshalalfa M, et al. Associations of luminal and basal subtyping of prostate cancer with prognosis and response to androgen deprivation therapy. JAMA Oncol. 2017;3:1663.
Karnes RJ, Sharma V, Choeurng V, Ashab HAD, Erho N, Alshalalfa M, et al. Development and validation of a prostate cancer genomic signature that predicts early ADT treatment response following radical prostatectomy. Clin Cancer Res. 2018;24:3908–16.
Wang C, Zhang Y, Gao WQ. The evolving role of immune cells in prostate cancer. Cancer Lett. 2022;525:9–21.
Chen S, Zhu G, Yang Y, Wang F, Xiao YT, Zhang N, et al. Single-cell analysis reveals transcriptomic remodellings in distinct cell types that contribute to human prostate cancer progression. Nat Cell Biol. 2021;23:87–98.
Obradovic AZ, Dallos MC, Zahurak ML, Partin AW, Schaeffer EM, Ross AE, et al. T-cell infiltration and adaptive Treg resistance in response to androgen deprivation with or without vaccination in localized prostate cancer. Clin Cancer Res. 2020;26:3182–92.
Mami-Chouaib F, Blanc C, Corgnac S, Hans S, Malenica I, Granier C, et al. Resident memory T cells, critical components in tumor immunology. J Immunother cancer. 2018;6:87.
Kvedaraite E, Ginhoux F. Human dendritic cells in cancer. Sci Immunol. 2022;7:eabm9409.
Floc’h AL, Jalil A, Franciszkiewicz K, Validire P, Vergnon I, Mami-Chouaib F. Minimal engagement of CD103 on cytotoxic T lymphocytes with an E-cadherin-Fc molecule triggers lytic granule polarization via a phospholipase Cγ-dependent pathway. Cancer Res. 2011;71:328–38.
Kinashi T. Intracellular signalling controlling integrin activation in lymphocytes. Nat Rev Immunol. 2005;5:546–59.
Webb JR, Milne K, Nelson BH. PD-1 and CD103 are widely coexpressed on prognostically favorable intraepithelial CD8 T cells in human ovarian cancer. Cancer Immunol Res. 2015;3:926–35.
Ganesan AP, Clarke J, Wood O, Garrido-Martin EM, Chee SJ, Mellows T, et al. Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. Nat Immunol. 2017;18:940–50.
Salmon H, Idoyaga J, Rahman A, Leboeuf M, Remark R, Jordan S, et al. Expansion and activation of CD103 + dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity. 2016;44:924–38.
Lai C, Coltart G, Shapanis A, Healy C, Alabdulkareem A, Selvendran S, et al. CD8+CD103+ tissue-resident memory T cells convey reduced protective immunity in cutaneous squamous cell carcinoma. J Immunother Cancer. 2021;9:e001807.
Chen R, Xie L, Xue W, Ye Z, Ma L, Gao X, et al. Development and external multicenter validation of Chinese Prostate Cancer Consortium prostate cancer risk calculator for initial prostate biopsy. Urologic Oncol: Semin Orig Investig. 2016;34:416.e1–416.e7.
Chen R, Zhou LQ, Cai XB, Xie LP, Huang YR, He DL, et al. Percent free prostate-specific antigen is effective to predict prostate biopsy outcome in Chinese men with prostate-specific antigen between 10.1 and 20.0 ng ml−1. Asian J Androl. 2015;17:1017.
Leclerc BG, Charlebois R, Chouinard G, Allard B, Pommey S, Saad F, et al. CD73 expression is an independent prognostic factor in prostate cancer. Clin Cancer Res. 2016;22:158–66.
Burugu S, Gao D, Leung S, Chia SK, Nielsen TO. LAG-3+ tumor infiltrating lymphocytes in breast cancer: clinical correlates and association with PD-1/PD-L1+ tumors. Ann Oncol. 2017;28:2977–84.
Mell LK, Meyer JJ, Tretiakova M, Khramtsov A, Gong C, Yamada SD, et al. Prognostic significance of E-cadherin protein expression in pathological stage I-III endometrial cancer. Clin Cancer Res. 2004;10:5546–53.
Lotan TL, Antonarakis ES. CDK12 deficiency and the immune microenvironment in prostate cancer. Clin Cancer Res. 2021;27:380–2.
Cao Y, He H, Li R, Liu X, Chen Y, Qi Y, et al. Latency-associated peptide identifies immunoevasive subtype gastric cancer with poor prognosis and inferior chemotherapeutic responsiveness. Ann Surg. 2022;275:e163–73.
Gevensleben H, Dietrich D, Golletz C, Steiner S, Jung M, Thiesler T, et al. The Immune checkpoint regulator PD-L1 is highly expressed in aggressive primary prostate cancer. Clin Cancer Res. 2016;22:1969–77.
Chen Y, Ma L, He Q, Zhang S, Zhang C, Jia W. TGF-β1 expression is associated with invasion and metastasis of intrahepatic cholangiocarcinoma. Biol Res. 2015;48:26.
Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7.
Yoshihara K, Shahmoradgoli M, Martínez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.
Troy A, Davidson P, Atkinson C, Hart D. Phenotypic characterisation of the dendritic cell infiltrate in prostate cancer. J Urol. 1998;160:214–9.
Petitprez F, Fossati N, Vano Y, Freschi M, Becht E, Lucianò R, et al. PD-L1 expression and CD8+ T-cell infiltrate are associated with clinical progression in patients with node-positive prostate cancer. Eur Urol Focus. 2019;5:192–6.
Boutet M, Gauthier L, Leclerc M, Gros G, de Montpreville V, Théret N, et al. TGFβ signaling intersects with CD103 integrin signaling to promote T-lymphocyte accumulation and antitumor activity in the lung tumor microenvironment. Cancer Res. 2016;76:1757–69.
Mokrani M, Klibi J, Bluteau D, Bismuth G, Mami-Chouaib F. Smad and NFAT pathways cooperate to induce CD103 expression in human CD8 T lymphocytes. J Immunol. 2014;192:2471–9.
Schiewer MJ, Goodwin JF, Han S, Brenner JC, Augello MA, Dean JL, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2012;2:1134–49.
Shafi AA, Schiewer MJ, de Leeuw R, Dylgjeri E, McCue PA, Shah N, et al. Patient-derived models reveal impact of the tumor microenvironment on therapeutic response. Eur Urol Oncol. 2018;1:325–37.
El-Kenawi A, Dominguez-Viqueira W, Liu M, Awasthi S, Abraham-Miranda J, Keske A, et al. Macrophage-derived cholesterol contributes to therapeutic resistance in prostate cancer. Cancer Res. 2021;81:5477–90.
Masopust D, Soerens AG. Tissue-resident T cells and other resident leukocytes. Annu Rev Immunol. 2019;37:521–46.
Wang B, Wu S, Zeng H, Liu Z, Dong W, He W, et al. CD103 + tumor infiltrating lymphocytes predict a favorable prognosis in urothelial cell carcinoma of the bladder. J Urol. 2015;194:556–62.
Boorjian SA, Karnes RJ, Viterbo R, Rangel LJ, Bergstralh EJ, Horwitz EM, et al. Long-term survival after radical prostatectomy versus external-beam radiotherapy for patients with high-risk prostate cancer. Cancer. 2011;117:2883–91.
Webb JR, Milne K, Watson P, deLeeuw RJ, Nelson BH. Tumor-infiltrating lymphocytes expressing the tissue resident memory marker CD103 are associated with increased survival in high-grade serous ovarian cancer. Clin Cancer Res. 2014;20:434–44.
Wang ZQ, Milne K, Derocher H, Webb JR, Nelson BH, Watson PH. CD103 and Intratumoral immune response in breast cancer. Clin Cancer Res. 2016;22:6290–7.
Locati M, Curtale G, Mantovani A. Diversity, mechanisms, and significance of macrophage plasticity. Annu Rev Pathol Mech Dis. 2020;15:123–47.
Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11:889–96.
Antonarakis ES, Piulats JM, Gross-Goupil M, Goh J, Ojamaa K, Hoimes CJ, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study. JCO. 2020;38:395–405.
van der Leun AM, Thommen DS, Schumacher TN. CD8+ T cell states in human cancer: insights from single-cell analysis. Nat Rev Cancer. 2020;20:218–32.
Gabriely G, da Cunha AP, Rezende RM, Kenyon B, Madi A, Vandeventer T, et al. Targeting latency-associated peptide promotes antitumor immunity. Sci Immunol. 2017;2:eaaj1738.
Ouyang W, O’Garra A. IL-10 family cytokines IL-10 and IL-22: from basic science to clinical translation. Immunity. 2019;50:871–91.
de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991;174:1209–20.
Smith LK, Boukhaled GM, Condotta SA, Mazouz S, Guthmiller JJ, Vijay R, et al. Interleukin-10 directly inhibits CD8+ T cell function by enhancing N-glycan branching to decrease antigen sensitivity. Immunity. 2018;48:299–312.e5.
Jiang C, Yuan F, Wang J, Wu L. Oral squamous cell carcinoma suppressed antitumor immunity through induction of PD-L1 expression on tumor-associated macrophages. Immunobiology. 2017;222:651–7.
Srinivasan S, Kumar R, Koduru S, Chandramouli A, Damodaran C. Inhibiting TNF-mediated signaling: a novel therapeutic paradigm for androgen independent prostate cancer. Apoptosis. 2010;15:153–61.
Di Mitri D, Mirenda M, Vasilevska J, Calcinotto A, Delaleu N, Revandkar A, et al. Re-education of tumor-associated macrophages by CXCR2 blockade drives senescence and tumor inhibition in advanced prostate cancer. Cell Rep. 2019;28:2156–2168.e5.
Yang C, Jin J, Yang Y, Sun H, Wu L, Shen M, et al. Androgen receptor-mediated CD8+ T cell stemness programs drive sex differences in antitumor immunity. Immunity. 2022;55:1268–1283.e9.
Kwon H, Schafer JM, Song NJ, Kaneko S, Li A, Xiao T, et al. Androgen conspires with the CD8 + T cell exhaustion program and contributes to sex bias in cancer. Sci Immunol. 2022;7:eabq2630.
Guan X, Polesso F, Wang C, Sehrawat A, Hawkins RM, Murray SE, et al. Androgen receptor activity in T cells limits checkpoint blockade efficacy. Nature. 2022;606:791–6.
This work was supported by the National Natural Science Foundation of China (Nos. 81872102, 82002720 and 81802569).
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The study was conducted by Huashan Hospital, Fudan University. All tissue-related experiments were in accordance with the regulations of the tissue bank and the study protocol was approved by the Huashan Hospital Institutional Review Board (KY2011-009). The study followed the ethical principles of the Declaration of Helsinki and signed informed consent was obtained from the participants.
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The original online version of this article was revised: There was an error in the scale bar in Figure 4g “Dendritic Cell” (right panel). The scale bar should be “50um”, not “100um”. The error occurred during typesetting.
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Zhou, Q., Ou, Y., Dai, X. et al. Prevalence of tumour-infiltrating CD103+ cells identifies therapeutic-sensitive prostate cancer with poor clinical outcome. Br J Cancer 128, 1466–1477 (2023). https://doi.org/10.1038/s41416-023-02183-4