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Article

PD-L1 Overexpression, SWI/SNF Complex Deregulation, and Profound Transcriptomic Changes Characterize Cancer-Dependent Exhaustion of Persistently Activated CD4+ T Cells

1
Department of Experimental Immunotherapy, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
2
Department of Pathology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
3
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland
4
Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
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Department of Biomedicine, University Hospital Basel and University of Basel, 4001 Basel, Switzerland
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Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
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Department of Gastroenterology, Hepatology and Clinical Oncology, Centre of Postgraduate Medical Education, 01-826 Warsaw, Poland
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Department of Oncology and Internal Medicine, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
9
Department of Lymphoid Malignancies, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this paper.
Academic Editors: Armand Bensussan and Andrea Cavazzoni
Cancers 2021, 13(16), 4148; https://doi.org/10.3390/cancers13164148
Received: 29 June 2021 / Revised: 4 August 2021 / Accepted: 13 August 2021 / Published: 18 August 2021
(This article belongs to the Special Issue Mechanisms of Tumor Immune Evasion)
Growing tumors induce an immune response. For proper immune response, both CD8+ and CD4+ effector T cells are required. Tumors avoid attacks from tumor-infiltrating lymphocytes (TILs) via induction of several inhibitory signals, such as PD-L1/2, which bind to the PD-1 receptor, consequently leading to T cell dysfunction, exhaustion, and apoptosis. The mechanism of T cell exhaustion has been studied mostly in CD8+ T cells, although some results suggest that CD4+ effector T cells also undergo exhaustion. In this study, we analyze global transcript profiling, PD-1 and PD-L1 expression, and chromatin status on the PD-L1 locus. We find that in exhausted CD4+ T cells, the levels of PD-L1 are increased at both the transcript and protein levels, while PD-L1 expression depends on SWI/SNF chromatin remodeling and PRC2-repressive complexes. The expression of PD-L1 in exhausted CD4+ T cells can be reversible.
Growing tumors avoid recognition and destruction by the immune system. During continuous stimulation of tumor-infiltrating lymphocytes (TILs) by tumors, TILs become functionally exhausted; thus, they become unable to kill tumor cells and to produce certain cytokines and lose their ability to proliferate. This collectively results in the immune escape of cancer cells. Here, we show that breast cancer cells expressing PD-L1 can accelerate exhaustion of persistently activated human effector CD4+ T cells, manifesting in high PD-1 and PD-L1 expression level son T cell surfaces, decreased glucose metabolism genes, strong downregulation of SWI/SNF chromatin remodeling complex subunits, and p21 cell cycle inhibitor upregulation. This results in inhibition of T cell proliferation and reduction of T cell numbers. The RNAseq analysis on exhausted CD4+ T cells indicated strong overexpression of IDO1 and genes encoding pro-inflammatory cytokines and chemokines. Some interleukins were also detected in media from CD4+ T cells co-cultured with cancer cells. The PD-L1 overexpression was also observed in CD4+ T cells after co-cultivation with other cell lines overexpressing PD-L1, which suggested the existence of a general mechanism of CD4+ T cell exhaustion induced by cancer cells. The ChIP analysis on the PD-L1 promoter region indicated that the BRM recruitment in control CD4+ T cells was replaced by BRG1 and EZH2 in CD4+ T cells strongly exhausted by cancer cells. These findings suggest that epi-drugs such as EZH2 inhibitors may be used as immunomodulators in cancer treatment. View Full-Text
Keywords: CD4+ effector T cells; T cell exhaustion; SWI/SNF complex; PD-1; PD-L1; PD-L1/PD-1 axis CD4+ effector T cells; T cell exhaustion; SWI/SNF complex; PD-1; PD-L1; PD-L1/PD-1 axis
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MDPI and ACS Style

Jancewicz, I.; Szarkowska, J.; Konopinski, R.; Stachowiak, M.; Swiatek, M.; Blachnio, K.; Kubala, S.; Oksinska, P.; Cwiek, P.; Rusetska, N.; Tupalska, A.; Zeber-Lubecka, N.; Grabowska, E.; Swiderska, B.; Malinowska, A.; Mikula, M.; Jagielska, B.; Walewski, J.; Siedlecki, J.A.; Sarnowski, T.J.; Markowicz, S.; Sarnowska, E.A. PD-L1 Overexpression, SWI/SNF Complex Deregulation, and Profound Transcriptomic Changes Characterize Cancer-Dependent Exhaustion of Persistently Activated CD4+ T Cells. Cancers 2021, 13, 4148. https://doi.org/10.3390/cancers13164148

AMA Style

Jancewicz I, Szarkowska J, Konopinski R, Stachowiak M, Swiatek M, Blachnio K, Kubala S, Oksinska P, Cwiek P, Rusetska N, Tupalska A, Zeber-Lubecka N, Grabowska E, Swiderska B, Malinowska A, Mikula M, Jagielska B, Walewski J, Siedlecki JA, Sarnowski TJ, Markowicz S, Sarnowska EA. PD-L1 Overexpression, SWI/SNF Complex Deregulation, and Profound Transcriptomic Changes Characterize Cancer-Dependent Exhaustion of Persistently Activated CD4+ T Cells. Cancers. 2021; 13(16):4148. https://doi.org/10.3390/cancers13164148

Chicago/Turabian Style

Jancewicz, Iga, Joanna Szarkowska, Ryszard Konopinski, Malgorzata Stachowiak, Monika Swiatek, Katarzyna Blachnio, Szymon Kubala, Paulina Oksinska, Pawel Cwiek, Natalia Rusetska, Agnieszka Tupalska, Natalia Zeber-Lubecka, Ewa Grabowska, Bianka Swiderska, Agata Malinowska, Michal Mikula, Beata Jagielska, Jan Walewski, Janusz A. Siedlecki, Tomasz J. Sarnowski, Sergiusz Markowicz, and Elzbieta A. Sarnowska 2021. "PD-L1 Overexpression, SWI/SNF Complex Deregulation, and Profound Transcriptomic Changes Characterize Cancer-Dependent Exhaustion of Persistently Activated CD4+ T Cells" Cancers 13, no. 16: 4148. https://doi.org/10.3390/cancers13164148

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