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

Workel, Hagma H.; Komdeur, Fenne L.; Wouters, Maartje C.A.; Plat, Annechien; Klip, Harry G.; Eggink, Florine A.; Wisman, G. Bea A.; Arts, Henriëtte J.G.; Oonk, Maaike H. M.; Mourits, Marian J.E.; Yigit, Refika; Versluis, Marco; Duiker, Evelien W.; Hollema, Harry; Bruyn, Marco de; Nijman, Hans W.

doi:10.1016/j.ejca.2016.02.026

Cited by 114 publications

(121 citation statements)

References 18 publications

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“…In human cervical cancer, a strong correlation between expression of CD103 and exhaustion molecules such as PD-1, TIGIT, LAG-3 and Tim-3 has been observed using the Cancer Genome Atlas [93]. This result has been confirmed at the protein level in ovarian and endometrial adenocarcinomas [26, 79]. Other checkpoint receptors (NKG2A, CD39, adenosine receptor A2AR and SPRY1) may also be preferentially expressed by T RM cells [14, 38].…”

Section: Role Of Trm In Immune Surveillance and Immunotherapymentioning

confidence: 93%

“…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

213

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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Section: Role Of Trm In Immune Surveillance and Immunotherapymentioning

confidence: 93%

Section: Role Of Trm In Immune Surveillance and Immunotherapymentioning

confidence: 99%

Section: Role Of Trm In Immune Surveillance and Immunotherapymentioning

confidence: 99%

See 1 more Smart Citation

Resident memory T cells, critical components in tumor immunology

Mami‐Chouaib¹,

Blanc²,

Corgnac³

et al. 2018

j. immunotherapy cancer

213

186

View full text Add to dashboard Cite

show abstract

“…Intra-epithelial CD8 + T cell density has shown independent prognostic significance in initial studies [181–183], and stromal CD3 + T cells may also have prognostic value [184]. Workel and colleagues demonstrated that CD103, a marker discussed further below, defined intra-epithelial CD8+ PD-1+ lymphocytes, and that high numbers of these iTILs were associated with improved prognosis in patients with high-risk endometrial adenocarcinoma [185]. High T reg counts were associated with poorer disease free survival in the study of Yamagami et al [186].…”

Section: Tils In Gynecological Carcinomasmentioning

confidence: 99%

Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non–Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors

Hendry

Salgado

Gevaert

et al. 2017

Advances in Anatomic Pathology

571

366

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Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecological system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

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“…The TCGA was then queried for expression of immune markers to validate this finding, and the POLE-mutant and MSI-high subsets demonstrated significantly higher levels of CD3, CD8 and other immune cell markers, confirming the relationship between tumor subset and immune infiltration. These findings contribute to the growing body of evidence suggesting that higher neoantigen load and higher somatic mutational load correlates with tumor sensitivity to immune-based therapies [66–69]. As we continue to learn more about the molecular profiles of endometrial cancer, we may be better able to characterize tumors amenable to immune-based approaches, including TIL therapy, for future studies.…”

Section: Adoptive T Cell Transfer In Uterine Cancermentioning

confidence: 69%

Adoptive cell transfer using autologous tumor infiltrating lymphocytes in gynecologic malignancies

Mayor

Starbuck

Zsiros

2018

Gynecologic Oncology

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During the last decade, the field of cancer immunotherapy has been entirely transformed by the development of new and more effective treatment modalities with impressive response rates and the prospect of long survival. One of the major breakthroughs is adoptive cell transfer (ACT) based on autologous T cells derived from tumor-infiltrating lymphocytes (TILs). TIL-based ACT is a highly personalized cancer treatment. T cells are harvested from autologous fresh tumor tissues, and after ex vivo activation and extensive expansion, are reinfused to patients. TIL-based therapies have only been offered in small phase I/II studies in a few centers given the highly specialized care required, the complexity of TIL production and the very intensive nature of the three-step treatment protocol. The treatment includes high-dose lymphodepleting chemotherapy, the infusion of the expanded and activated T cells and interleukin-2 (IL-2) injections to increase survival of the T cells. Despite the limited data on ACT, the small published studies consistently confirm an impressive clinical response rate of up to 50 % in metastatic melanoma patients, including a significant proportion of patients with durable complete response. These remarkable results justify the need for larger clinical trials in other solid tumors, including gynecologic malignancies. In this review we provide an overview of the current clinical results, future applications of TIL-based ACT in gynecologic malignancies, and on risks and challenges associated with modern T cell therapy.

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

Cited by 114 publications

References 18 publications

Resident memory T cells, critical components in tumor immunology

Resident memory T cells, critical components in tumor immunology

Adoptive cell transfer using autologous tumor infiltrating lymphocytes in gynecologic malignancies

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