CD4+ T cells in classical Hodgkin lymphoma express exhaustion associated transcription factors TOX and TOX2

Abstract

In classical Hodgkin lymphoma (cHL), the highly abundant CD4+ T cells in the vicinity of tumor cells are considered essential for tumor cell survival, but are ill-defined. Although they are activated, they consistently lack expression of activation marker CD26. In this study, we compared sorted CD4+CD26- and CD4+CD26+ T cells from cHL lymph node cell suspensions by RNA sequencing and T cell receptor variable gene segment usage analysis. This revealed that although CD4+CD26- T cells are antigen experienced, they have not clonally expanded. This may well be explained by the expression of exhaustion associated transcription factors TOX and TOX2 , immune checkpoints PDCD1 and CD200 , and chemokine CXCL13 , which were amongst the 100 significantly enriched genes in comparison with the CD4+CD26+ T cells. Findings were validated in single-cell RNA sequencing data from an independent cohort. Interestingly, immunohistochemistry revealed predominant and high frequency of staining for TOX and TOX2 in the T cells attached to the tumor cells. In conclusion, the dominant CD4+CD26- T cell population in cHL is antigen experienced, polyclonal, and exhausted. This population is likely a main contributor to the very high response rates to immune checkpoint inhibitors in cHL.

TOX regulates T lymphocytes differentiation and its function in tumor

“…The necessity of TOX for CD4 lineage development suggests that its abnormal expression may lead to clonal proliferation of malignant T tumor cells. There is extensive evidence that abnormal TOX expression leads to lymphoma development ( 8 , 22 , 47 ), especially T-lymphoma. The effects of TOX on cutaneous T-cell lymphoma (CTCL) have been studied extensively ( 31 – 35 ).…”

TOX as a new diagnostic marker for T cell large granular lymphocytic leukaemia

“…[11][12][13] TOX expression is not restricted to chronic infections; it also develops in CD8 + and CD4 + T cells in the tumour microenvironment (TME) of various malignancies. 13,14 Expression of TOX has been found in several types of lymphoma, including both B and T cell subtypes. 13,15,16 Huuhtanen et al 17 The goal of this study is to investigate the extent of TOX expression in T-LGLL cells, and whether TOX expression can be used to differentiate between T-LGLL cells and reactive T cells in bone marrow.…”

“…13,14 Expression of TOX has been found in several types of lymphoma, including both B and T cell subtypes. 13,15,16 Huuhtanen et al 17 The goal of this study is to investigate the extent of TOX expression in T-LGLL cells, and whether TOX expression can be used to differentiate between T-LGLL cells and reactive T cells in bone marrow.…”

The value of thymus and activation related chemokine immunohistochemistry in classic Hodgkin lymphoma diagnostics

“…This expression is much higher than the physiological expression by normal dendritic and epithelial cells of the thymus 5 . TARC binds to the CC chemokine receptor 4 (CCR4) on CD4 + T cells and strongly contributes to the characteristic T cell‐rich tumour micro‐environment of cHL 6 . Because of the high secretion of TARC by HRS cells, approximately 85% of cHL patients have elevated serum or plasma levels at diagnosis compared to healthy controls (median ~400× higher).…”

“… 5 TARC binds to the CC chemokine receptor 4 (CCR4) on CD4 + T cells and strongly contributes to the characteristic T cell‐rich tumour micro‐environment of cHL. 6 Because of the high secretion of TARC by HRS cells, approximately 85% of cHL patients have elevated serum or plasma levels at diagnosis compared to healthy controls (median ~400× higher). Elevated TARC levels correspond with higher‐stage disease and tumour volume.…”