CD103 defines intraepithelial CD8+ PD1+ tumour-infiltrating lymphocytes of prognostic significance in endometrial adenocarcinoma

Published:March 31, 2016DOI:


      • CD103 is a marker for intraepithelial CD8+ T-cells in endometrial carcinoma (EC).
      • The presence of CD103+ T-cells is associated with improved survival in EC.
      • CD8+CD103+ T-cells are antigen-experienced and widely express PD1.
      • The potential of CD103 as a population for adoptive transfer immunotherapy should be investigated further.



      Intraepithelial CD8+ tumour-infiltrating T-lymphocytes (TIL) are associated with a prolonged survival in endometrial cancer (EC). By contrast, stromal infiltration of CD8+ TIL does not confer prognostic benefit. A single marker to discriminate these populations would therefore be of interest for rapid assessment of the tumour immune contexture, ex vivo analysis of intraepithelial and stromal T-cells on a functional level and/or adoptive T-cell transfer. Here we determined whether CD103, the αE subunit of the αEβ7integrin, can be used to specifically discriminate the epithelial and stromal CD8+ TIL populations in EC.


      CD103+ TIL were quantified in a cohort of 305 EC patients by immunohistochemistry. Localization of CD103+ cells and co-expression of CD103 with CD3, CD8, CD16 and FoxP3 were assessed by immunofluorescence. Further phenotyping of CD103+ cells was performed by flow cytometry on primary endometrial tumour digests.


      CD8+CD103+ cells were preferentially located in endometrial tumour epithelium, whereas CD8+CD103− cells were located in stroma. CD103+ lymphocytes were predominantly CD3+CD8+ T-cells and expressed PD1. The presence of a high CD103+ cell infiltration was associated with an improved prognosis in patients with endometrial adenocarcinoma (p = 0.035). Moreover, this beneficial effect was particularly evident in high-risk adenocarcinoma patients (p = 0.031).


      Because of the restricted expression on intraepithelial CD8+ T-cells, CD103 may be a suitable biomarker for rapid assessment of immune infiltration of epithelial cancers. Furthermore, this intraepithelial tumour-reactive subset might be an interesting T-cell subset for adoptive T-cell transfer and/or target for checkpoint inhibition therapy.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Jemal A.
        • Bray F.
        • Center M.M.
        • Ferlay J.
        • Ward E.
        • Forman D.
        Global cancer statistics.
        CA Cancer J Clin. 2011 Mar-Apr; 61: 69-90
        • Colombo N.
        • Preti E.
        • Landoni F.
        • Carinelli S.
        • Colombo A.
        • Marini C.
        • et al.
        Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2013; 24: vi33-vi38
        • Kondratiev S.
        • Sabo E.
        • Yakirevich E.
        • Lavie O.
        • Resnick M.B.
        Intratumoral CD8+ T lymphocytes as a prognostic factor of survival in endometrial carcinoma.
        Clin Cancer Res. 2004; 10: 4450-4456
        • de Jong R.A.
        • Leffers N.
        • Boezen H.M.
        • ten Hoor K.A.
        • van der Zee A.G.
        • Hollema H.
        • et al.
        Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer.
        Gynecol Oncol. 2009; 114: 105-110
        • Chang W.C.
        • Li C.H.
        • Huang S.C.
        • Chang D.Y.
        • Chou L.Y.
        • Sheu B.C.
        Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma.
        Cancer. 2010; 116: 5777-5788
        • Karecla P.I.
        • Green S.J.
        • Bowden S.J.
        • Coadwell J.
        • Kilshaw P.J.
        Identification of a binding site for integrin alphaEbeta7 in the N-terminal domain of E-cadherin.
        J Biol Chem. 1996; 271: 30909-30915
        • Cepek K.L.
        • Shaw S.K.
        • Parker C.M.
        • Russell G.J.
        • Morrow J.S.
        • Rimm D.L.
        • et al.
        Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin.
        Nature. 1994; 372: 190-193
        • Le Floc'h A.
        • Jalil A.
        • Vergnon I.
        • Le Maux Chansac B.
        • Lazar V.
        • Bismuth G.
        • et al.
        Alpha E beta 7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis.
        J Exp Med. 2007; 204: 559-570
        • Cepek K.L.
        • Parker C.M.
        • Madara J.L.
        • Brenner M.B.
        Integrin alpha E beta 7 mediates adhesion of T lymphocytes to epithelial cells.
        J Immunol. 1993; 150: 3459-3470
        • Franciszkiewicz K.
        • Le Floc'h A.
        • Jalil A.
        • Vigant F.
        • Robert T.
        • Vergnon I.
        • et al.
        Intratumoral induction of CD103 triggers tumor-specific CTL function and CCR5-dependent T-cell retention.
        Cancer Res. 2009; 69: 6249-6255
        • Le Floc'h A.
        • 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 Cgamma-dependent pathway.
        Cancer Res. 2011; 71: 328-338
        • Franciszkiewicz K.
        • Le Floc'h A.
        • Boutet M.
        • Vergnon I.
        • Schmitt A.
        • Mami-Chouaib F.
        CD103 or LFA-1 engagement at the immune synapse between cytotoxic T cells and tumor cells promotes maturation and regulates T-cell effector functions.
        Cancer Res. 2013; 73: 617-628
        • Djenidi F.
        • Adam J.
        • Goubar A.
        • Durgeau A.
        • Meurice G.
        • de Montpreville V.
        • et al.
        CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T Cells and a prognostic factor for survival in lung cancer patients.
        J Immunol. 2015; 194: 3475-3486
        • Webb J.R.
        • Milne K.
        • Watson P.
        • Deleeuw R.J.
        • Nelson B.H.
        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: 434-444
        • Wang B.
        • Shaoxu W.
        • Zeng H.
        • Liu Z.
        • Dong W.
        • Wang H.
        • et al.
        CD103 tumor-infiltrating lymphocytes predict a favorable prognosis in urothelial cell carcinoma of the bladder.
        J Urol. 2015;
        • Webb J.R.
        • Wick D.A.
        • Nielsen J.S.
        • Tran E.
        • Milne K.
        • McMurtrie E.
        • et al.
        Profound elevation of CD8+ T cells expressing the intraepithelial lymphocyte marker CD103 (alphaE/beta7 Integrin) in high-grade serous ovarian cancer.
        Gynecol Oncol. 2010 Sep; 118: 228-236
        • Webb J.R.
        • Milne K.
        • Nelson B.H.
        PD-1 and CD103 are widely co-expressed on prognostically favorable intraepithelial CD8 T cells in human ovarian cancer.
        Cancer Immunol Res. 2015;
        • van Gool I.C.
        • Eggink F.A.
        • Freeman-Mills L.
        • Stelloo E.
        • Marchi E.
        • de Bruyn M.
        • et al.
        POLE proofreading mutations elicit an anti-tumor immune response in endometrial cancer.
        Clin Cancer Res. 2015;
        • Rosenberg S.A.
        • Yang J.C.
        • Sherry R.M.
        • Kammula U.S.
        • Hughes M.S.
        • Phan G.Q.
        • et al.
        Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy.
        Clin Cancer Res. 2011; 17: 4550-4557