CD161 expression and regulation defines rapidly responding effector CD4+ T cells associated with improved survival in HPV16-associated tumors.

Autor:	Duurland CL; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., Santegoets SJ; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., Abdulrahman Z; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., Loof NM; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., Sturm G; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria., Wesselink TH; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands., Arens R; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands., Boekestijn S; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., Ehsan I; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., van Poelgeest MIE; Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands., Finotello F; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria.; Institute of Molecular Biology, University of Innsbruck, Innsbruck, Austria.; Digital Science Center (DiSC), University of Innsbruck, Innsbruck, Austria., Hackl H; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria., Trajanoski Z; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria., Ten Dijke P; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands., Braud VM; Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, UMR7275, 06560 Valbonne, Sophia Antipolis, France., Welters MJP; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., van der Burg SH; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands shvdburg@lumc.nl.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Jan; Vol. 10 (1).
DOI:	10.1136/jitc-2021-003995
Abstrakt:	Background: Expression of killer cell lectin-like receptor B1 ( KLRB1 ), the gene encoding the cell surface molecule CD161, is associated with favorable prognosis in many cancers. CD161 is expressed by several lymphocyte populations, but its role and regulation on tumor-specific CD4+ T cells is unknown. Methods: We examined the clinical impact of CD4+CD161+ T cells in human papillomavirus (HPV)16+ oropharyngeal squamous cell carcinoma (OPSCC), analyzed their contribution in a cohort of therapeutically vaccinated patients and used HPV16-specific CD4+CD161+ tumor-infiltrating lymphocytes and T cell clones for in-depth mechanistic studies. Results: Central and effector memory CD4+ T cells express CD161, but only CD4+CD161+ effector memory T cells (Tem) are associated with improved survival in OPSCC. Therapeutic vaccination activates and expands type 1 cytokine-producing CD4+CD161+ effector T cells. The expression of CD161 is dynamic and follows a pattern opposite of the checkpoint molecules PD1 and CD39. CD161 did not function as an immune checkpoint molecule as demonstrated using multiple experimental approaches using antibodies to block CD161 and gene editing to knockout CD161 expression. Single-cell transcriptomics revealed KLRB1 expression in many T cell clusters suggesting differences in their activation. Indeed, CD4+CD161+ effector cells specifically expressed the transcriptional transactivator SOX4, known to enhance T cell receptor (TCR) signaling via CD3ε. Consistent with this observation, CD4+CD161+ cells respond more vigorously to limiting amounts of cognate antigen in presence of interleukin (IL)-12 and IL-18 compared to their CD161- counterparts. The expression of CD161/ KLRB1 and SOX4 was downregulated upon TCR stimulation and this effect was boosted by transforming growth factor (TGF)β1. Conclusion: High levels of CD4+CD161+ Tem are associated with improved survival and our data show that CD161 is dynamically regulated by cell intrinsic and extrinsic factors. CD161 expressing CD4+ T cells rapidly respond to suboptimal antigen stimulation suggesting that CD161, similar to SOX4, is involved in the amplification of TCR signals in CD4+ T cells. Competing Interests: Competing interests: GS reports personal fees from Pieris Pharmaceuticals GmbH outside the submitted work. FF has received honoraria for lecturing at the ESMO Virtual Advanced Course on Biomarkers for Precision Medicine 2021. PtD reports grants from Oncode Institute and Cancer Genomics Center Netherlands (CGC.NL). VMB reports funding from Centre National de la Recherche Scientifique, French Government (National Research Agency, ANR) through the 'Investments for the Future' programs LABEX SIGNALIFE ANR-11-LABX-0028 and IDEX UCAJedi ANR-15-IDEX-01, Cancéropole PACA and Fondation ARC pour la recherche sur le Cancer. SHvdB reports grants from IO Biotech and DC Prime for immunemonitoring of trials and personal consulting fees from ISA Pharmaceuticals, PCI Biotech, DC Prime, CHDR consultancy services and AGLAIA outside the submitted work. The other authors declare no conflict of interest. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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