CD103
            <sup>+</sup>
            Tumor Infiltrating Lymphocytes Predict a Favorable Prognosis in Urothelial Cell Carcinoma of the Bladder

Wang, Bo; Wu, Shaoxu; Zeng, Hong; Liu, Zhuowei; Dong, Wen; Wang, He; Chen, Zhanghua; Dong, Xiaoliang; Zheng, Limin; Lin, Tianxin; Huang, Jian

doi:10.1016/j.juro.2015.02.2941

Cited by 142 publications

(139 citation statements)

References 29 publications

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“…It was first identified in association with intraepithelial CD8 T cells and has been shown to be upregulated in CD8 T cells after antigen stimulation, but can also be expressed by regulatory FoxP3-positive CD4 T cells and by activated dendritic cells (12). Nevertheless, our studies in ovarian cancer show that the majority of CD103-positive cells are CD8 T cells and similar findings were reported in lung, colorectal, and bladder cancer (13)(14)(15)(16). CD103 expression on CD8 T cells is upregulated in response to simultaneous TGFb1 stimulation and antigen recognition (17).…”

Section: Introductionsupporting

confidence: 86%

CD103 and Intratumoral Immune Response in Breast Cancer

Wang

Milne

Derocher

et al. 2016

Clinical Cancer Research

132

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Purpose: CD103 is expressed in several immune cell types but in the context of the intratumoral immune response may be most important as a marker of antigen-activated CD8 T cells.Methods: We have examined the prognostic significance of CD103 TILs in breast cancer by IHC in a cohort of 424 breast cancer patients.Results: CD103 TILs were present in all subtypes but were more abundant in ER-negative tumors where CD103 TILs were preferentially localized to the intraepithelial compartment. CD103 was associated with tumor size, tumor grade, and ER/PR status (P < 0.05). CD103 TIL density and the epithelial to stromal ratio was highest in the basal-like tumors. Intraepithelial CD103 but not intrastromal CD103 was associated with better relapse-free and overall survival in basal-like subtype tumors [HR ¼ 0.28; 95% confidence interval (CI), 0.17-0.72; P ¼ 0.0047 and HR ¼ 0.25; 95% CI, 0.17-0.66; P ¼ 0.0017, respectively). CD8 status showed similar but less significant associations, but the combination of dual CD103 þ CD8þ TIL status was the most strongly prognostic combination for relapse-free and overall survival (HR ¼ 0.10; 95% CI, 0.07-0.62; P ¼ 0.006 and HR ¼ 0.09; 95% CI, 0.07-0.57; P ¼ 0.003, respectively). Conclusions: CD103 TILs are indicative of a good prognosis specifically within the basal-like subtype of breast cancer. Clin Cancer Res; 22(24); 6290-7. Ó2016 AACR.

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Section: Introductionsupporting

confidence: 86%

CD103 and Intratumoral Immune Response in Breast Cancer

Wang

Milne

Derocher

et al. 2016

Clinical Cancer Research

132

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“…Along the same lines, an enhanced CD103 + TIL subset correlated with increased intraepithelial lymphocyte infiltration [26, 27], supporting the hypothesis that CD103 promotes recruitment of T RM cells within epithelial tumor islets. The intra-epithelial location of CD103 + CD8 + T cells was also observed in colorectal and bladder cancers, and was associated with expression of E-cadherin on tumor cells [28, 29]. Consistently, studies performed with viable human tumor slices [30] and autologous tumor antigen-specific CTL clones showed that CD103 contributes to T-cell recruitment within epithelial tumor regions and enhances intratumoral T-cell early signaling [31].…”

Section: Introductionmentioning

confidence: 79%

“…These cells are also found in various tumors, including melanoma [78], lung cancer [27, 39], urothelial cell carcinoma [29] and endometrial adenocarcinoma [79]. Tumors with a high density of CD8 + T cells showed enrichment for transcripts linked to tissue-T-cell-residency, such as CD103 [38].…”

Section: Role Of Trm In Immune Surveillance and Immunotherapymentioning

confidence: 99%

“…However, there exists phenotypic heterogeneity in T RM cells according to their location and tumor histological subtype. In all subtypes of endometrial adenocarcinoma, CD8 + TIL were present in both the tumor epithelium and stromal areas, but the frequency of CD8 + CD103 + T cells was significantly higher in the tumor epithelium than in the stroma [27, 29, 79]. Most CD103 + cells in the tumor microenvironment co-express the CD8 molecule, whereas CD8 + TIL located in the stroma were mainly negative for CD103 integrin.…”

Section: Role Of Trm In Immune Surveillance and Immunotherapymentioning

confidence: 99%

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Resident memory T cells, critical components in tumor immunology

Mami‐Chouaib¹,

Blanc²,

Corgnac³

et al. 2018

j. immunotherapy cancer

227

186

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CD8+ T lymphocytes are the major anti-tumor effector cells. Most cancer immunotherapeutic approaches seek to amplify cytotoxic T lymphocytes (CTL) specific to malignant cells. A recently identified subpopulation of memory CD8+ T cells, named tissue-resident memory T (TRM) cells, persists in peripheral tissues and does not recirculate. This T-cell subset is considered an independent memory T-cell lineage with a specific profile of transcription factors, including Runx3+, Notch+, Hobit+, Blimp1+, BATF+, AHR+, EOMESneg and Tbetlow. It is defined by expression of CD103 (αE(CD103)β7) and CD49a (VLA-1 or α1β1) integrins and C-type lectin CD69, which are most likely involved in retention of TRM cells in non-lymphoid tissues, including solid tumors. CD103 binds to the epithelial cell marker E-cadherin, thereby favoring the location and retention of TRM in epithelial tumor regions in close contact with malignant cells. The CD103-E-cadherin interaction is required for polarized exocytosis of lytic granules, in particular, when ICAM-1 expression on cancer cells is missing, leading to target cell death. TRM cells also express high levels of granzyme B, IFNγ and TNFα, supporting their cytotoxic features. Moreover, the local route of immunization targeting tissue dendritic cells (DC), and the presence of environmental factors (i.e. TGF-β, IL-33 and IL-15), promote differentiation of this T-cell subtype. In both spontaneous tumor models and engrafted tumors, natural TRM cells or cancer-vaccine-induced TRM directly control tumor growth. In line with these results, TRM infiltration into various human cancers, including lung cancer, are correlated with better clinical outcome in both univariate and multivariate analyses independently of CD8+ T cells. TRM cells also predominantly express checkpoint receptors such as PD-1, CTLA-4 and Tim-3. Blockade of PD-1 with neutralizing antibodies on TRM cells isolated from human lung cancer promotes cytolytic activity toward autologous tumor cells. Thus, TRM cells appear to represent important components in tumor immune surveillance. Their induction by cancer vaccines or other immunotherapeutic approaches may be critical for the success of these treatments. Several arguments, such as their close contact with tumor cells, dominant expression of checkpoint receptors and their recognition of cancer cells, strongly suggest that they may be involved in the success of immune checkpoint inhibitors in various cancers.

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“…Reports have demonstrated that a high number of tumour‐infiltrating T RM cells is linked to improved prognosis in patients with urinary bladder, lung, cervical and ovarian cancers [7, 8, 9, 10]. The improved prognosis is due to the capacity of T RM cells to produce IFN‐γ upon in‐situ antigen recognition [11], resulting in the recruitment of circulating T cells from the blood [12].…”

Section: Introductionmentioning

confidence: 99%

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

Hartana

Bergman

Broomé

et al. 2018

Clinical and Experimental Immunology

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SummaryTissue‐resident memory T (TRM) cells are CD8+ T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in TRM cells and correlate it with their functional potential. Fifty‐three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in TRM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in‐vitro stimulation were used to evaluate TRM cell phenotypes. We discovered that tumour TRM cells have low DNA methylation in the PRF1 locus (32·9% methylation), which corresponds to increased numbers of perforin‐expressing TRM cells. Surprisingly, programmed cell death 1 (PD‐1) expression is high in tumour TRM cells, suggesting exhaustion. Following interleukin‐15 and T cell receptor stimulation, perforin and T‐bet expressions are enhanced, indicating that TRM cells from tumours are not terminally exhausted. Moreover, a high number of TRM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, TRM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies TRM cells as potential new targets for cancer immunotherapy.

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CD103 ⁺ Tumor Infiltrating Lymphocytes Predict a Favorable Prognosis in Urothelial Cell Carcinoma of the Bladder

Cited by 142 publications

References 29 publications

CD103 and Intratumoral Immune Response in Breast Cancer

CD103 and Intratumoral Immune Response in Breast Cancer

Resident memory T cells, critical components in tumor immunology

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

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CD103 + Tumor Infiltrating Lymphocytes Predict a Favorable Prognosis in Urothelial Cell Carcinoma of the Bladder

Cited by 142 publications

References 29 publications

CD103 and Intratumoral Immune Response in Breast Cancer

CD103 and Intratumoral Immune Response in Breast Cancer

Resident memory T cells, critical components in tumor immunology

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

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CD103 ⁺ Tumor Infiltrating Lymphocytes Predict a Favorable Prognosis in Urothelial Cell Carcinoma of the Bladder