PD-1+ Polyfunctional T Cells Dominate the Periphery after Tumor-Infiltrating Lymphocyte Therapy for Cancer

Marco Donia; Julie Westerlin Kjeldsen; Rikke Andersen; Marie Christine Wulff Westergaard; Valentina Bianchi; Mateusz Legut; Meriem Attaf; Barbara Szomolay; Sascha Ott; Garry Dolton; Rikke Lyngaa; Sine Reker Hadrup; Andrew K Sewell; Inge Marie Svane

doi:10.1158/1078-0432.ccr-16-1692

PD-1⁺ Polyfunctional T Cells Dominate the Periphery after Tumor-Infiltrating Lymphocyte Therapy for Cancer

Marco Donia, Julie Westerlin Kjeldsen, Rikke Andersen, Marie Christine Wulff Westergaard, Valentina Bianchi, Mateusz Legut, Meriem Attaf, Barbara Szomolay, Sascha Ott, Garry Dolton, Rikke Lyngaa, Sine Reker Hadrup, Andrew K Sewell, Inge Marie Svane

Department of Clinical Medicine

23 Citations (Scopus)

Abstract

Purpose: Infusion of highly heterogeneous populations of autologous tumor-infiltrating lymphocytes (TIL) can result in tumor regression of exceptional duration. Initial tumor regression has been associated with persistence of tumor-specific TILs 1 month after infusion, but mechanisms leading to long-lived memory responses are currently unknown. Here, we studied the dynamics of bulk tumor-reactive CD8^þ T-cell populations in patients with metastatic melanoma following treatment with TILs. Experimental Design: We analyzed the function and phenotype of tumor-reactive CD8^þ T cells contained in serial blood samples of 16 patients treated with TILs. Results: Polyfunctional tumor-reactive CD8^þ 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^þ T cells, with highly specific PD-1 upregulation early after infusion. The differentiation and functional status appeared largely stable for up to 1 year after infusion. Despite some degree of clonal diversification occurring in vivo within the bulk tumor-reactive CD8^þ T cells, further analyses showed that CD8^þ T cells specific for defined tumor antigens had similar differentiation status. Conclusions: We demonstrated that tumor-reactive CD8^þ T-cell subsets that 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^þ polyfunctional TILs have a high capacity for persistence and may be susceptible to PD-L1/PD-L2–mediated inhibition.

Original language	English
Journal	Clinical Cancer Research
Volume	23
Issue number	19
Pages (from-to)	5779-5788
ISSN	1078-0432
DOIs	https://doi.org/10.1158/1078-0432.ccr-16-1692
Publication status	Published - 1 Oct 2017

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Donia, M., Kjeldsen, J. W., Andersen, R., Westergaard, M. C. W., Bianchi, V., Legut, M., Attaf, M., Szomolay, B., Ott, S., Dolton, G., Lyngaa, R., Hadrup, S. R., Sewell, A. K., & Svane, I. M. (2017). PD-1⁺ Polyfunctional T Cells Dominate the Periphery after Tumor-Infiltrating Lymphocyte Therapy for Cancer. Clinical Cancer Research, 23(19), 5779-5788. https://doi.org/10.1158/1078-0432.ccr-16-1692

Donia, M, Kjeldsen, JW, Andersen, R, Westergaard, MCW, Bianchi, V, Legut, M, Attaf, M, Szomolay, B, Ott, S, Dolton, G, Lyngaa, R, Hadrup, SR, Sewell, AK & Svane, IM 2017, 'PD-1⁺ Polyfunctional T Cells Dominate the Periphery after Tumor-Infiltrating Lymphocyte Therapy for Cancer', Clinical Cancer Research, vol. 23, no. 19, pp. 5779-5788. https://doi.org/10.1158/1078-0432.ccr-16-1692

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title = "PD-1+ Polyfunctional T Cells Dominate the Periphery after Tumor-Infiltrating Lymphocyte Therapy for Cancer",

abstract = "Purpose: Infusion of highly heterogeneous populations of autologous tumor-infiltrating lymphocytes (TIL) can result in tumor regression of exceptional duration. Initial tumor regression has been associated with persistence of tumor-specific TILs 1 month after infusion, but mechanisms leading to long-lived memory responses are currently unknown. Here, we studied the dynamics of bulk tumor-reactive CD8{\th} T-cell populations in patients with metastatic melanoma following treatment with TILs. Experimental Design: We analyzed the function and phenotype of tumor-reactive CD8{\th} T cells contained in serial blood samples of 16 patients treated with TILs. Results: Polyfunctional tumor-reactive CD8{\th} 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{\th} T cells, with highly specific PD-1 upregulation early after infusion. The differentiation and functional status appeared largely stable for up to 1 year after infusion. Despite some degree of clonal diversification occurring in vivo within the bulk tumor-reactive CD8{\th} T cells, further analyses showed that CD8{\th} T cells specific for defined tumor antigens had similar differentiation status. Conclusions: We demonstrated that tumor-reactive CD8{\th} T-cell subsets that 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{\th} polyfunctional TILs have a high capacity for persistence and may be susceptible to PD-L1/PD-L2–mediated inhibition.",

author = "Marco Donia and Kjeldsen, {Julie Westerlin} and Rikke Andersen and Westergaard, {Marie Christine Wulff} and Valentina Bianchi and Mateusz Legut and Meriem Attaf and Barbara Szomolay and Sascha Ott and Garry Dolton and Rikke Lyngaa and Hadrup, {Sine Reker} and Sewell, {Andrew K} and Svane, {Inge Marie}",

note = "{\textcopyright}2017 American Association for Cancer Research.",

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doi = "10.1158/1078-0432.ccr-16-1692",

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pages = "5779--5788",

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T1 - PD-1+ Polyfunctional T Cells Dominate the Periphery after Tumor-Infiltrating Lymphocyte Therapy for Cancer

AU - Donia, Marco

AU - Kjeldsen, Julie Westerlin

AU - Andersen, Rikke

AU - Westergaard, Marie Christine Wulff

AU - Bianchi, Valentina

AU - Legut, Mateusz

AU - Attaf, Meriem

AU - Szomolay, Barbara

AU - Ott, Sascha

AU - Dolton, Garry

AU - Lyngaa, Rikke

AU - Hadrup, Sine Reker

AU - Sewell, Andrew K

AU - Svane, Inge Marie

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Purpose: Infusion of highly heterogeneous populations of autologous tumor-infiltrating lymphocytes (TIL) can result in tumor regression of exceptional duration. Initial tumor regression has been associated with persistence of tumor-specific TILs 1 month after infusion, but mechanisms leading to long-lived memory responses are currently unknown. Here, we studied the dynamics of bulk tumor-reactive CD8þ T-cell populations in patients with metastatic melanoma following treatment with TILs. Experimental Design: We analyzed the function and phenotype of tumor-reactive CD8þ T cells contained in serial blood samples of 16 patients treated with TILs. Results: Polyfunctional tumor-reactive CD8þ 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 CD8þ T cells, with highly specific PD-1 upregulation early after infusion. The differentiation and functional status appeared largely stable for up to 1 year after infusion. Despite some degree of clonal diversification occurring in vivo within the bulk tumor-reactive CD8þ T cells, further analyses showed that CD8þ T cells specific for defined tumor antigens had similar differentiation status. Conclusions: We demonstrated that tumor-reactive CD8þ T-cell subsets that persist after TIL therapy are mostly polyfunctional, display a stable partially differentiated phenotype, and express high levels of PD-1. These partially differentiated PD-1þ polyfunctional TILs have a high capacity for persistence and may be susceptible to PD-L1/PD-L2–mediated inhibition.

AB - Purpose: Infusion of highly heterogeneous populations of autologous tumor-infiltrating lymphocytes (TIL) can result in tumor regression of exceptional duration. Initial tumor regression has been associated with persistence of tumor-specific TILs 1 month after infusion, but mechanisms leading to long-lived memory responses are currently unknown. Here, we studied the dynamics of bulk tumor-reactive CD8þ T-cell populations in patients with metastatic melanoma following treatment with TILs. Experimental Design: We analyzed the function and phenotype of tumor-reactive CD8þ T cells contained in serial blood samples of 16 patients treated with TILs. Results: Polyfunctional tumor-reactive CD8þ 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 CD8þ T cells, with highly specific PD-1 upregulation early after infusion. The differentiation and functional status appeared largely stable for up to 1 year after infusion. Despite some degree of clonal diversification occurring in vivo within the bulk tumor-reactive CD8þ T cells, further analyses showed that CD8þ T cells specific for defined tumor antigens had similar differentiation status. Conclusions: We demonstrated that tumor-reactive CD8þ T-cell subsets that persist after TIL therapy are mostly polyfunctional, display a stable partially differentiated phenotype, and express high levels of PD-1. These partially differentiated PD-1þ polyfunctional TILs have a high capacity for persistence and may be susceptible to PD-L1/PD-L2–mediated inhibition.

U2 - 10.1158/1078-0432.ccr-16-1692

DO - 10.1158/1078-0432.ccr-16-1692

M3 - Journal article

C2 - 28679768

SN - 1078-0432

VL - 23

SP - 5779

EP - 5788

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 19

ER -