Antitumor CD8 T cell responses in glioma patients are effectively suppressed by T follicular regulatory cells
Introduction
Gliomas are malignant tumors primarily found in the brain but can occur in other parts of the central nervous system [1]. It is a relatively rare tumor type with an overall incidence ranging between 4.7 and 5.7 per 100,000 individuals [2]. Treatment usually involves surgery to remove the tumor mass followed by chemotherapy and radiation therapy [3]. Prognosis varies significantly by histologic types, tumor location, age, and grade at diagnosis [1]. Most gliomas occur in an apparently spontaneous fashion with no identifiable cause or genetic predisposition. To develop better therapeutic strategies, further research in the molecular and biological aspects of this disease is necessary.
T follicular regulatory (Tfr) cells are CD4 T cells that express both T follicular helper (Tfh) cell transcription factor (TF) Bcl-6 at a lower level and canonical T regulatory (Treg) cell TF Foxp3 [[4], [5], [6]]. Unlike Tfh cells, Tfr cells also express the Bcl-6 antagonist transcription factor Blimp-1. At the cell surface, Tfr cells express chemokine receptor CXCR5, checkpoint inhibitor PD-1, inhibitory receptor CTLA-4, costimulatory molecule ICOS, high-affinity IL-2 receptor CD25, but do not express CD127 [4,7]. These features enable Tfr cells colocalization with B cells and Tfh cells and potentiate Tfr cells to exert regulatory function toward humoral immunity [8]. Human CD4+CXCR5+CD25+CD127--sorted Tfr cells have demonstrated capacity to attenuate antibody responses in vitro [9]. Also, CD3+CD8−CXCR5+CD25+-sorted Tfr cells or CD4+CD25+ cells that migrated toward a CXCL13 gradient in Rhesus macaques can inhibit Tfh functions in vivo [10,11]. Mechanisms by which Tfr cells modulate B cell and Tfh cell responses include direct cell-to-cell contact and indirect modification of the microenvironment via cytokine expression and sequestration [10]. Deficiencies in Tfr cells are linked with the autoimmune diseases [12].
Interestingly, recent experiments indicate that Tfr cells also present regulatory roles toward antitumor responses. Tfr cells are found to infiltrate ovarian carcinoma [13]. Levels of regulatory cytokine expression, including TGF-β and IL-10, by Tfr cells, are inversely correlated with the level of IFN-γ expression by tumor-infiltrating CD8 T cells. In addition, Tfr cells could directly suppress CD8 T cell activation in vitro in an IL-10-dependent manner [13]. Related to this, it is shown that in the absence of Tfr cells, Tfh cells developed cytotoxic capacity with high granzyme B expression as well as upregulation in genes associated with effector CD8 T cells [14], which indicated that Tfr cells had the potential to downregulate cytotoxic response.
Based on the above findings, we questioned whether Tfr cells presented a role in anti-glioma immune responses. To investigate this question, we harvested tumor resections and circulating lymphocytes from glioma patients and investigated the characteristics and function of Tfr cells.
Section snippets
Study participants
To perform this study, twenty untreated patients with resectable pilocytic astrocytomas or diffuse astrocytomas and twenty healthy individuals were recruited at Shunde Hospital. The patient group and the control group were all adults (age between 18 and 65 years) with HLA-A*02 allele and were matched in age, male-to-female ratio, body-mass index, and ethnicity. Exclusion criteria were history of other malignancies, autoimmune diseases, cardiovascular diseases, and chronic virus infections.
Tfr cells were highly enriched in tumor-infiltrating lymphocytes compared to circulating lymphocytes
To examine the characteristics of Tfr cells, resected glioma tumor samples were obtained from twenty glioma patients to harvest tumor-infiltrating lymphocytes. For comparison, circulating lymphocytes were collected from the peripheral blood of those glioma patients and from the peripheral blood of healthy individuals. Tfr cells were identified as Foxp3+Bcl-6+ CD4+CD25+ T cells, whereas canonical Treg cells were identified as Foxp3+Bcl-6- CD4+CD25+ T cells (Fig. 1A). The proportion of each CD4 T
Discussion
Tfr cells are a recently characterized group of Treg cells with indispensable roles in regulating humoral responses at homeostasis and during inflammation [23]. Previous studies have shown that the main targets of Tfr cell-mediated suppression include germinal center B cells, plasma cells, and Tfh cells. In this study, we presented evidence that CXCR5+ CD8 T cells, a subset of CD8 T cells with elevated effector functions and reduced exhaustion marker expressions [20,24], were especially
Author contribution statement
Lenian Lu: Conceptualization; Data curation; Formal analysis; Writing – original draft; Writing – review & editing. Jie Sun: Conceptualization; Data curation; Formal analysis; Writing – review & editing. Hang Su: Conceptualization; Data curation; Formal analysis. Shi Luo: Data curation; Formal analysis. Jianmin Chen: Data curation; Formal analysis. Shengcong Qiu: Data curation; Formal analysis. Yajie Chi: Data curation; Formal analysis. Jiye Lin: Data curation; Formal analysis. Xiaobing Xu:
Declaration of competing interest
None.
Acknowledgments
This work was supported by Project of Clinical Outstanding Clinical Discipline Construction in Shanghai Pudong New Area (No. PWYgy2018-07), Project of Shanghai Municipality Key Medical Specialties Construction (No. ZK2019C08), and Leading Talent Training in Shanghai Pudong New Area Health System (No. PWRl2018-08).
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These authors contributed equally to the work.