PTEN deletion may be associated with CD8+ T-cell exhaustion in diffuse large B-cell lymphoma

doi:10.21203/rs.3.rs-2950216/v1

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PTEN deletion may be associated with CD8+ T-cell exhaustion in diffuse large B-cell lymphoma

https://doi.org/10.21203/rs.3.rs-2950216/v1

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'T-cell exhaustion' is a broad term describing the response of T cells to chronic antigen stimulation, initially in chronic viral infection and then extended to tumors. By definition, whether T-cell exhaustion occurs in diffuse large B-cell lymphoma (DLBCL) remains largely unknown because little has been described. Here, the immune-suppressing checkpoint molecules involved in T-cell exhaustion, including PD-1, PD-L1, TIM-3, IL-10, IL-6 and IL-2, whose expression levels were analyzed in DLBCL, were retrieved from the GEPIA database. Compared with the normal control, CD8A, TNFA, IFNG and GZMA were markedly elevated in DLBCL, indicating that infiltrated CD8+ T cells predominate in DLBCL. Meanwhile, inhibitory immune checkpoints, such as PD-1, PD-L1, TIM-3, IL-10, IL-6 and IL-2, were significantly higher in DLBCL. PTEN, WNT2, and DKK3 expression was also evaluated. It was revealed that PTEN was lower in DLBCL without being statistically significant. Standing in contrast with PTEN, DKK3 and WNT2 were shown to be pronouncedly higher in DLBCL relative to the normal control. Prognostically, the transcriptional levels of PTEN, CD8A and DKK3 were shown to be unassociated with overall survival in DLBCL. Together, all the data we curetted from the GEPIA and TIMER databases explicitly and strongly indicate that CD8+ T-cell exhaustion may occur, which may be linked with PTEN deletion in DLBCL. To the best of our knowledge, this is the first bioinformatic study explicitly proposing that T-cell exhaustion occurs in DLBCL, which is associated with PTEN loss.

diffuse large B-cell lymphoma (DLBCL)

T-cell exhaustion

PTEN

CD8+T

GEPIA.

T-cell exhaustion, which broadly refers to the dysfunctional state of T cells that initially originates in the setting of chronic infection and then extends to cancer, is characterized by a trio panel of poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector T cells [1, 2]. Once taking place, exhaustion of T cells can prevent optimal control of infection or tumors. Therefore, a better understanding of the features of T-cell exhaustion will be vitally important because it has crucial implications for the success of checkpoint blockade and adoptive T-cell transfer therapies in response to viral infection or tumor cells [2]. Recent developments in the field of T-cell exhaustion have led to a proliferation of studies performed in experimental and clinical settings; however, it remains largely unknown whether T-cell exhaustion occurs in diffuse large B-cell lymphoma (hereafter referred to as DLBCL). Considering that CD8 + T cells constitute an important branch of subpopulations for T cells, we chiefly focused on CD8 + T cells, regardless of the exhaustion of other T cells in DLBCL in the study.

Recently, a clearer picture of the functional and phenotypic profile of exhausted T cells has emerged, and T-cell exhaustion has been defined [2]. The first explicit indication that coexpression of TIGIT and PD-1 on T cells marks the reduced effector function was provided by Josefsson SE and associates [3] in DLBCL, showing that TIGIT and PD-1 mark dysfunctional T cells. Subsequent work separately contributed by Zhang TT et al [4] identified that positive expression of TIM3 on CD8 + T cells was held in a state of exhaustion, leading to inferior survival to that of which CD8 + T cells did express TIM3 in DLBCL. In support of this finding, Roussel M et al [5] confirmed in their own study that tumor-infiltrating T lymphocytes coexpressing PD-1 and TIM3 were exhausted in DLBCL. On the basis of the literature reviewed above together with bioinformatic analysis, we hypothesized that CD8 + T exhaustion could take place in the tumor microenvironment of DLBCL, which could be caused by PTEN deficiency. To the best of our knowledge, this is the first bioinformatic study explicitly proposing that CD8 + T-cell exhaustion occurs in DLBCL, which is linked to PTEN loss.

Expression of effector function

First, to understand the expression pattern of effector molecules, we retrieved CD8A, TNFA, INFG, and GZMA, which are classical effector molecules pertaining to cytotoxic CD8 + T cells, with the aid of the GEPIA database. All four classical effector biomarkers of CD8 + T cells were markedly upregulated in DLBCL tissues, numbering 47 cases compared with normal controls, totaling 337 cases (Fig. 1). These data suggest that the number of CD8 + T cells predominates in DLBCL relative to the normal control.

Expression of Inhibitory Immune Checkpoints

Hallmarked by sustained expression of inhibitory immune receptors, together with poor effector function plus a transcriptional state distinct from that of functional effector or memory T cells, T-cell exhaustion [1] can be said to take place. As one of the three hallmarks of T-cell exhaustion, the expression of inhibitory immune checkpoint molecules is essential to the occurrence of T-cell exhaustion. To understand the expression of inhibitory immune checkpoints, including TIGIT, PD-L1, PD-1 and TIM3, we retrieved data from DLBCL in the GEPIA database. TIGIT, PD-L1, PD-1 and TIM3 mRNA levels were all remarkably elevated in DLBCL compared with normal controls (Fig. 1), suggesting that CD8 + T cells infiltrated in the DLBCL tumor microenvironment might be exhausted in accordance with the definition of T-cell exhaustion[1].

Expression of cytokines driving T-cell exhaustion

Regarded as critical mediators in the tumor microenvironment, inflammatory cytokines, such as IL-2 [6], IL-10[7] and IL-6 [8] secreted from tumor cells, have been found to drive T-cell exhaustion. Despite these findings, the expression of IL-2, IL-10 and IL-6 has been rarely described and remains largely unknown. To investigate the expression of the three cytokines reported to be involved in T-cell exhaustion in DLBCL, using the GEPIA database, we retrieved the related data, discovering that IL-10 and IL-6 were significantly higher in DLBCL patients than in normal controls, while IL-2 was higher in DLBCL patients but with no significant difference (Fig. 2). The data presented here indicate that upregulation of IL-2, IL-10 and IL-6 might cause CD8 + T cells to live in a state of exhaustion in the tumor microenvironment of DLBCL.

Expression of PTEN, WNT2 and STAT3 in DLBCL

Although several studies revealed that abnormal PTEN, including deletion and mutation, has important implications for the pathogenesis of DLBCL [9, 10], little is known about PTEN expression at the mRNA level in DLBCL. We found that PTEN mRNA was lower in DLBCL than in normal controls, with the difference being nonsignificant (Fig. 2). In addition, abnormal WNT signaling [11] and signal transducer and activator (STAT) signaling [11] pathways were also identified as pivotal pathways in the pathogenesis and treatment of DLBCL. Correspondingly, we selected WNT2 and STAT3 as key nodes in their respective pathways to understand the expression status in DLBCL, showing that WNT2 was drastically upregulated in DLBCL compared with normal controls (Fig. 2). STAT3 mRNA levels were reduced in DLBCL relative to normal controls, but the difference was nonsignificant (Fig. 2). These data suggest activation of the WNT signaling pathway and the unknown role of the WNT pathway in mediating T-cell dysfunction in DLBCL.

Prognostic significance of biomarkers related to CD8 + T-cell exhaustion in DLBCL

Having understood the expression pattern of biomarkers we took interested in DLBCL, we next analyzed their expression status in different clinical stages, covering from stage I to stage IV, displaying that there were no statistically significant differences in expression in different clinical stages (Fig. 3). Subsequently, we sought to understand the prognostic significance of their expression at the mRNA level. Data from disease-free survival (DFS) analyses revealed that only higher expression of TIGIT was remarkably associated with shorter DFS in DLBCL. No significant association with DFS was identified for the remaining biomarkers (Fig. 4). Discouragingly, in overall survival (OS) analyses, none of these biomarkers we were concerned with were found to be significantly associated with OS in DLBCL (Fig. 5).

PTEN deficiency markedly correlated with the infiltration of CD8 + T cells in DLBCL

Next, we wondered whether there would be any correlation between the loss of PTEN and the infiltration of tumor-associated lymphocytes, such as M1 macrophages, CD8 + T cells, neutrophils and regulatory T (Treg) cells, in DLBCL. Driven by the question aroused, we analyzed the correlation by means of the TIMER database, displaying that PTEN deficiency positively and significantly correlated with the infiltration of M1 macrophages, CD8 + T cells, and neutrophils in DLBCL. However, there was a significant negative correlation between the loss of PTEN and the infiltration of Treg cells in DLBCL (Fig. 6). These data indicate that the lower PTEN expression was, the lower the number of CD8 + T cells and the more Treg cells were infiltrating. Furthermore, to confirm the correlation we observed at the cellular level, we next analyzed PTEN expression and effector molecules pertaining to cytotoxic CD8 + T cells at the molecular level, revealing that PTEN expression at the mRNA level positively and profoundly correlated with the expression of classical effector molecules, including CD8A and IFNG, in DLBCL. In addition, PTEN mRNA expression was also positively correlated with PD-L1, PD-L2, IL-10 and IL-6 expression at the mRNA level in DLBCL (Fig. 7). As verification, we further analyzed, using three different algorithms, the correlation between copying number variation (CNV) of PTEN at the DNA level, including deletion and gain, and infiltration of cytotoxic CD8 + T cells in DLBCL, demonstrating that the number of infiltrating CD8 + T cells was markedly decreased, along with the deletion of CNV of PTEN, and vice versa (Fig. 8). It should be noted that we did not find a significant correlation between the variation in the CNV of PTEN and the infiltration of M1 macrophages, neutrophils and Treg cells in DLBCL (data now shown).

In this study, to understand whether T-cell exhaustion could take place in DLBCL, RNA-sequencing data associated with the features of T-cell exhaustion, including effector molecules and inhibitory receptors, were mined by means of the GEPIA and TIMER 2.0 databases. Compared with normal controls, TNFA, IFNG and GZMA, all three classical effector molecules of cytotoxic CD8 + T cells were found to be dramatically reduced in DLBCL. Meanwhile, the inhibitory receptors we obtained, including TIGIT, TIM3, PD-L1 and PD-1, whose expression was significantly elevated in DLBCL. Moreover, some important inflammatory cytokines were reported to be capable of promoting T-cell exhaustion, for instance, IL-10 and IL-6, whose expression was markedly reduced in DLBCL relative to the normal control. Notably, CD8A and FOXP3, reflecting the infiltrated status of CD8 and Treg cells, were expectedly downregulated in DLBCL in comparison with the normal control. In addition, DKK3 and WNT2, two key members of the WNT signaling pathway involved in T-cell exclusion in the tumor microenvironment, were found to be profoundly upregulated in DLBCL. Aside from these key molecules described above, both PTEN and STAT3, the two important molecules we have been focusing on and interested in, were shown to be lower in DLBCL, but without being statistically significant, in comparison with the normal control. Taken together, all these data we gleaned explicitly and strongly indicate that T-cell exhaustion took place in DLBCL.

The original observation describing the phenomenon of exhausted T cells came from the human immunodeficiency virus (HIV) infection study [12], which led to a proliferation of literature concerning T-cell exhaustion since the publication of this observation. Subsequently, this phenomenon was rapidly and extensively reproduced in both human and animal models infected with human hepatitis B virus (HBV) and hepatitis C virus (HCV)[7], other than HIV infection. Notably, observations regarding T-cell exhaustion were made from virus infection[13] to tumors [14] wherein T-cell dysfunction or exhaustion also existed. A great deal of studies revealed that T-cell exhaustion took place in tumors, including hematologic malignancies [3, 15, 16] as well as solid tumors [17, 18], albeit mechanistically less well-known. To understand the nuts and bolts of the big picture regarding T-cell exhaustion, we refer the readers to previous seminal reviews [1, 19] written on molecular and cellular insights into T-cell exhaustion, and here, we mainly focus our discussion on more recent findings with respect to CD8 + T-cell exhaustion [20, 21] that occurred in DLBCL. Marked by the continuous loss of effectors (such as PRF1, GZMB, and TNFA) and the expression of multiple inhibitory receptors (e.g., PD-1, LAG3, and TIGIT) [21, 22], CD8 + T-cell exhaustion was tentatively deemed to be occurring. In our study, taking advantage of available data regarding DLBCL from the GEPIA and TIMER databases, we showed canonical effector molecules of cytotoxic CD8 + T cells, including CD8A, TNFA, IFNG and GZMA, whose mRNA levels were strikingly upregulated in DLBCL tissues in comparison with normal controls. Interestingly, immune inhibitory receptors, including TIGIT[3], PD-1[3], PD-L1, and TIM3[5], were also remarkably elevated in DLBCL, along with the upregulation of inflammatory cytokines, including IL-2 [23], IL-6 [24]and IL-10[25], which have been reported to actively participate in CD8 T + cell exhaustion.

Considering these findings, we hypothesized that T-cell exhaustion could take place in the tumor microenvironment of DLBCL. Despite the hypothesis we proposed here lacking experimental evidence supporting it, Chen B et al [15] detected, using immunostaining, the expression of immune checkpoint molecules, including PD-1, PD-L1, TIM-3 and LAG-3, demonstrating that the four checkpoints were all markedly higher in DLBCL than in normal controls, which was totally in support of our bioinformatic data. However, we did not find any significant difference in survival, regardless of DFS or OS, regarding the expression of PD-1, PD-L1 and TIM-3. Similar conclusions can also be found in other published literature [26, 27].

Prognositcally, among all biomarkers we were interested in in this study, only TIGIT, whose mRNA expression level was shown to be pronouncedly associated with survival of DLBCL, in terms of disease-free survival (DFS). For the remainder, a nonsignificant association can be observed with survival. It would be somewhat discouraging to exhibit that in overall survival (OS) analysis, no significant association can be found between mRNA expression of biomarkers we were concerned with and overall survival of DLBCL. Inconsistent with our data, Nakayama S et al [28] evaluated the expression of TNFA in 62 cases of DLBCL tissues using immunohistochemistry and concluded that TNFA expression was a significant predictor for OS and DFS in DLBCL. Similar to TNFA, there was also some controversy regarding the prognostic significance of PD-L1 expression, with some [29, 30] supporting that PD-L1 expression can be significantly predictive of OS or DFS, while others [27, 31, 32] showed a nonsignificant association of PD-L1 with survival in DLBCL. In addition to PD-L1, the same can be applied to TIM3 in DLBCL, with some [15] supporting while others [26] negating the prognostic significance of TIM3 expression in DLBCL. Regarding PTEN mRNA expression, we did not find a significant difference in survival in DLBCL. The same was true for Foxp3, WNT2, DKK3, STAT3 and inflammatory cytokines, including IL-10 and IL-6.

Notably, deletion of PTEN has been revealed to be linked with immune suppression [33] and T-cell exclusion [34] in the tumor microenvironment. Suggested by these reports, we therefore explored the correlation of PTEN expression with the infiltration of tumor-infiltrating lymphocytes we were most concerned with, showing that there was a significantly positive correlation between PTEN expression and the infiltration of M1 macrophages, CD8 + T cells and neutrophils in DLBCL. For Treg cells, a significantly negative correlation can be observed between PTEN expression level and infiltration of Treg cells, meaning that the lower the expression of PTEN was, the less infiltration of CD8 + T cells will be; conversely, the more Treg cells will be infiltrating the tumor microenvironment of DLBCL. Fundamentally consistent with these findings, there were profoundly positive correlations between PTEN expression and CD8A, IFNG, PD-L1, PD-L2, IL-10 and IL-6 in DLBCL. On the other hand, a question naturally aroused here is whether PTEN loss is the sole cause of the immune suppression of CD8 + T cells in tumors. Combining these findings with the related literature seems to suggest that it is not necessarily the only reason.

Apart from PTEN deficiency, an abnormal Wnt/β-catenin signaling pathway in tumor cells has been repeatedly demonstrated to be responsible for T-cell exclusion or dysfunction in various types of tumors [35–38]. Given these findings, special attention was given to WNT2 and DKK3, which are inhibitor molecules of the Wnt/β-catenin pathway, in DLBCL, and WNT2 was significantly higher, along with DKK3, in DLBCL than in normal controls. The data we gleaned here explicitly indicate that the Wnt/β-catenin pathway was partly activated [39], which might play a crucial role in preventing CD8 + T cells from infiltrating the tumor microenvironment of DLBCL. In addition, the signal transducer and activator (STAT) signaling pathway [11] is another pivotal pathway involved in the pathogenesis of DLBCL. STAT3 mRNA expression was lower in DLBCL than in normal controls, but the difference was not statistically significant. Moreover, no significant difference in survival was observed between high and low mRNA expression of STAT3 in DLBCL. Our data were different from the study by Fei Y et al [40], who reported that soluble PD-L1 and STAT3 derived from plasma can predict the prognosis in DLBCL. In light of this controversy, in studies that follow, more work needs to be done to determine the prognostic significance of STAT3, no matter what level it is on, including transcriptional, translational and posttranslational modification.

In closing, in this study, we hypothesized that PTEN deficiency may be linked to CD8 + T-cell exhaustion in the tumor microenvironment of DLBCL on the basis of available data curetted from the GEPIA and TIMER databases. We analyzed, from a bioinformatic perspective, the expression and correlation between PTEN expression and some classical effector molecules pertaining to cytotoxic CD8 + T cells, including CD8A, TNFA, IFNG and GZMA; some inhibitory immune checkpoint molecules, such as TIGIT, PD-L1, PD-1, and TIM3; and some cytokines implicated in T-cell exhaustion, such as IL-10, IL-6 and IL-2, in DLBCL. Importantly, we also evaluated the prognostic significance of these biomarkers, revealing that only TIGIT was markedly associated with DFS in DLBCL. In light of the bioinformatic analyses, our hypothesis obviously requires strengthening using both in vitro and in vivo experimental evidence.

Gene expression of biomarkers related to T cell exhaustion.

The GEPIA (Gene Expression Profiling Interactive Analysis) database[41] (http://gepia.cancer-pku.cn/) was used to analyze the expression and prognostic significance of canonical effector molecules of cytotoxic CD8 + T cells (CD8A, TNFA, IFNG and GZMA), inhibitory immune checkpoint molecules (TIGIT, PD-1, PD-L1, and TIM3), inflammatory cytokines implicated in T-cell exhaustion (IL-10, IL-6 and IL-2), and PTEN, WNT2, DKK3, STAT3 and Foxp3, representing regulatory T cells in DLBCL.

Prognosis Analysis

Overall survival (OS) and disease-free survival (DFS) Kaplan–Meier plots of PTEN and other biomarkers related to T cell exhaustion in all TCGA tumor types, were produced using the Gene Expression Profiling Interactive Analysis version 2 (GEPIA2) (http://gepia2.cancer-pku.cn/). The expression threshold was set at 50% for high expression and low expression.

Immune correlation analyses between PTEN and biomarkers related to T cell exhaustion.

The Tumor Immune Estimation Resource (TIMER) database[42] (http://timer.cistrome.org/) was employed to analyze the correlation of the expression of PTEN at the mRNA level and the infiltration level of tumor-associated lymphocytes, including M1 macrophages, CD8 + T cells, neutrophils and regulatory T cells, in DLBCL, in addition to analyzing the correlation between the infiltration of CD8 + T cells and copying number variations of PTEN at the DNA level.

Statistical analysis

Gene expression comparisons made between the tumor and normal control groups were performed using two-sided Welch’s t test; for differential gene expression at different clinical stages covering from stage I to stage IV, homogeneity of variances was verified by F test, followed by one-way ANOVA with Bonferroni post hoc test performed under equal conditions. Correlation analysis was performed using the Pearson correlation coefficient, unless otherwise specified. The Kruskal‒Wallis test was adopted to analyze the correlation between copying number variation of PTEN on DNA level and infiltration of CD8 + T cells. Survival curves were plotted using the Kaplan‒Meier method, and differences in survival were analyzed by the log-rank approach. Differences were considered statistically significant if the P score was less than 0.05.

Acknowledgment

We wish to acknowledge the help from staffs, serving in the department of Pathology for their support behind, thought whose names were not appeared in the authorship. In addition, great thanks go to databases, such as GEPIA and TIMER 2.0 we are working with.

Authors’ contribution

SZ and WC conceived the idea; SZ and JM drafted the manuscript; XP, JL and MM retrieved the bioinformatic database; ZM revised the manuscript; WC was in charge of whole study.

Funding

This study was supported by the grant National Science Foundation of China (No. 82060038) and partly from the grant Science Foundation of Xinjiang Uyghur Autonomous Region (No. 2020D01A119).

Availability of data and materials

All the data related to the manuscript were presented. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

Not Applicable.

Human ethics

Not Applicable.

Consent for publication

Not Applicable.

Competing interests

The authors declare that they have no competing interest.

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No competing interests reported.

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PTEN deletion may be associated with CD8+ T-cell exhaustion in diffuse large B-cell lymphoma

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Version 1

Abstract

Figures

Introduction

Results

Expression of effector function

Expression of Inhibitory Immune Checkpoints

Expression of cytokines driving T-cell exhaustion

Expression of PTEN, WNT2 and STAT3 in DLBCL

Prognostic significance of biomarkers related to CD8 + T-cell exhaustion in DLBCL

PTEN deficiency markedly correlated with the infiltration of CD8 + T cells in DLBCL

Discussion

Conclusion

Materials and methods

Prognosis Analysis

Statistical analysis

Declarations

References

Additional Declarations

Status:

Version 1