TOX as a potential target for immunotherapy in lymphocytic malignancies

Liang, Chaofeng; Huang, Shuxin; Zhao, Yujie; Chen, Shaohua; Li, Yangqiu

doi:10.1186/s40364-021-00275-y

Cited by 40 publications

(36 citation statements)

References 53 publications

(51 reference statements)

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“…It is important for the differentiation of subsets of T-cells and natural killer cells. It is also implicated in tumor development as it induces CD8+ T-cell exhaustion by weakening their effector functions [ 18 ]. T-cell exhaustion occurs when cytotoxic T-cells are constantly activated, such as in cancer and chronic viral infection.…”

Section: Discussionmentioning

confidence: 99%

“…TOX is overexpressed in tumor infiltrating cells and is associated with an increased expression of the inhibitory programmed-death protein. In malignant T-cell lymphomas, TOX is highly expressed in MF, T-lymphoblastic lymphoma, angioimmunoblastic T-cell lymphoma, and in a lower level in peripheral T-cell lymphoma and other lymphomas [ 18 , 19 , 20 ]. What drives TOX expression and its role in MF is unclear.…”

Section: Discussionmentioning

confidence: 99%

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Immunohistochemical Expression Patterns of CD45RO, p105/p50, JAK3, TOX, and IL-17 in Early-Stage Mycosis Fungoides

et al. 2022

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The morphologic changes in early-stage mycosis fungoides (MF) might overlap with benign inflammatory dermatitis (BID). Previous studies have described altered expression patterns of several proteins in MF, but their diagnostic significance is uncertain. This study aims at examining the frequency of expression of CD45RO, NFkB-p105/p50, JAK3, TOX, and IL-17 proteins by immunohistochemistry. The cohorts included 21 patients of early-stage MF and 19 with benign BID as a control group. CD45RO was positive in all patients of MF and BID. NFkB-p105/p50 showed normal cytoplasmic staining, indicating an inactive status in all patients of both groups. JAK3 was positive in 3 (14%) MF and in 17 (89%) BID patients (p = 0.003). TOX was expressed in 19 (90%) and 13 (68%) patients of MF and BID, respectively (p = 0.120). IL-17 was detected in 13 (62%) MF and in 7 (37%) BID patients (p = 0.056). Co-expression of TOX and IL-17 was seen in 11 (52%) MF patients but in only 3 (16%) BID patients, which was statistically significant (p = 0.021). We conclude that a double expression of TOX and IL-17 may support the diagnosis of MF in the right clinicopathologic setting, while none of the immunohistochemical stains alone provided a significant discrimination between MF and BID.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Immunohistochemical Expression Patterns of CD45RO, p105/p50, JAK3, TOX, and IL-17 in Early-Stage Mycosis Fungoides

et al. 2022

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“…The biomarkers for AML outcome, particularly those related to immune suppression, which often occurs in cancer immune escape, are far from clear. Recent studies have shown that TOX is a crucial transcription factor that contributes to T cell exhaustion and is involved in tumor development (16,23). However, how TOX is altered in AML remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…TOX includes four subfamily members (TOX1-4, TOX1 is also known as TOX) (15). TOX is a crucial transcription factor related to the development of malignancies and contributing to CD8+ T cell exhaustion in patients with solid tumors (16)(17)(18). For example, TOX is positively correlated with larger tumor size, lower differentiation, later tumor node metastasis (TNM) stage, and facilitating endocytic recycling of PD-1 (17).…”

Section: Introductionmentioning

confidence: 99%

Higher TOX Genes Expression Is Associated With Poor Overall Survival for Patients With Acute Myeloid Leukemia

et al. 2021

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Thymocyte selection-associated HMG box (TOX) is a transcription factor that belongs to the high mobility group box (HMG-box) superfamily, which includes four subfamily members: TOX, TOX2, TOX3, and TOX4. TOX is related to the formation of multiple malignancies and contributes to CD8+ T cell exhaustion in solid tumors. However, little is known about the role of TOX genes in hematological malignancies. In this study, we explored the prognostic value of TOX genes from 40 patients with de novo acute myeloid leukemia (AML) by quantitative real-time PCR (qRT-PCR) in a training cohort and validated the results using transcriptome data from 167 de novo AML patients from the Cancer Genome Atlas (TCGA) database. In the training cohort, higher expression of TOX and TOX4 was detected in the AML samples, whereas lower TOX3 expression was found. Moreover, both the training and validation results indicated that higher TOX2, TOX3, and TOX4 expression of AML patients (3-year OS: 0% vs. 37%, P = 0.036; 3-year OS: 4% vs. 61%, P < 0.001; 3-year OS: 0% vs. 32%, P = 0.010) and the AML patients with highly co-expressed TOX, TOX2, TOX4 genes (3-year OS: 0% vs. 25% vs. 75%, P = 0.001) were associated with poor overall survival (OS). Interestingly, TOX2 was positively correlated with CTLA-4, PD-1, TIGIT, and PDL-2 (rs = 0.43, P = 0.006; rs = 0.43, P = 0.006; rs = 0.56, P < 0.001; rs = 0.54, P < 0.001). In conclusion, higher expression of TOX genes was associated with poor OS for AML patients, which was related to the up-regulation of immune checkpoint genes. These data might provide novel predictors for AML outcome and direction for further investigation of the possibility of using TOX genes in novel targeted therapies for AML.

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“…The TOX protein family consists of four members that all function as transcription factors: TOX (also known as TOX1), TOX2, TOX3 and TOX4. 32 TOX and/or TOX2 are involved in many early lymphoid developmental processes, including positive selection in thymocytes, early development of CD4+ T and NK cells, development of innate lymphoid cells and lymph node organogenesis. 33–35 More important in the setting of our study, they are essential for the development of Tfh cells and the induction of exhaustion in both CD4+ and CD8+ T cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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.

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TOX as a potential target for immunotherapy in lymphocytic malignancies

Cited by 40 publications

References 53 publications

Immunohistochemical Expression Patterns of CD45RO, p105/p50, JAK3, TOX, and IL-17 in Early-Stage Mycosis Fungoides

Immunohistochemical Expression Patterns of CD45RO, p105/p50, JAK3, TOX, and IL-17 in Early-Stage Mycosis Fungoides

Higher TOX Genes Expression Is Associated With Poor Overall Survival for Patients With Acute Myeloid Leukemia

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

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