PD-1+ polyfunctional T cells dominate the periphery after tumour-infiltrating lymphocyte therapy for cancer

Donia, Marco, Kjeldsen, Julie Westerlin, Andersen, Rikke, Wulff Westergaard, Marie Christine, Bianchi, Valentina, Legut, Mateusz, Attaf, Meriem, Szomolay, Barbara ORCID: https://orcid.org/0000-0002-5375-5533, Ott, Sascha, Dolton, Garry, Lyngaa, Rikke, Hadrup, Sine Reker, Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135 and Svane, Inge Marie 2017. PD-1+ polyfunctional T cells dominate the periphery after tumour-infiltrating lymphocyte therapy for cancer. Clinical Cancer Research 23 (19) , pp. 5779-5788. 10.1158/1078-0432.CCR-16-1692

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Abstract

Purpose: Infusion of highly heterogeneous populations of autologous tumor-infiltrating lymphocytes (TILs) can result in tumor regression of exceptional duration. Initial tumor regression has been associated with persistence of tumor-specific TILs one month after infusion, but mechanisms leading to long-lived memory responses are currently unknown. Here we studied the dynamics of bulk tumor-reactive CD8+ T cell populations in patients with metastatic melanoma following treatment with TILs. Experimental Design: We analyzed the function and phenotype of tumor-reactive CD8+ T cells contained in serial blood samples of sixteen patients treated with TILs Results: Polyfunctional tumor-reactive CD8+ T cells accumulated over time in the peripheral lymphocyte pool. Combinatorial analysis of multiple surface markers (CD57, CD27, CD45RO, PD- 1 and LAG-3) showed a unique differentiation pattern of polyfunctional tumor-reactive CD8+ T cells, with highly specific PD-1 upregulation early after infusion. The differentiation and functional status appeared largely stable for up to 1 year post-infusion. Despite some degree of clonal diversification occurring in vivo within the bulk tumor-reactive CD8+ T cells, further analyses showed that CD8+ T cells specific for defined tumor-antigens had similar differentiation status. Conclusions: We demonstrated that tumor-reactive CD8+ T cell subsets which persist after TIL therapy are mostly polyfunctional, display a stable partially differentiated phenotype and express high levels of PD-1. These partially differentiated PD-1+ polyfunctional TILs have a high capacity for persistence and may be susceptible to PD-L1/PD-L2-mediated inhibition.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	American Association for Cancer Research
ISSN:	1078-0432
Funders:	Wellcome Trust
Date of First Compliant Deposit:	19 July 2017
Date of Acceptance:	26 June 2017
Last Modified:	13 Nov 2024 16:45
URI:	https://orca.cardiff.ac.uk/id/eprint/102640

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