The identification of TCF1+ progenitor exhausted T-cells in THRLBCL may predict a better response to PD-1/PD-L1 blockade
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PROVIDER: PRJNA848231 | ENA |
REPOSITORIES: ENA
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Project description:T-cell/histiocyte rich large B-cell lymphoma (THRLBCL) is a rare and aggressive variant of diffuse large B cell lymphoma (DLBCL) that usually affects young to middle-aged patients, with disseminated disease at presentation. The tumor microenvironment (TME) plays a key role in THRLBCL, due to its peculiar cellular composition (less than 10% neoplastic B-cells interspersed in a cytotoxic T-cell/histiocyte rich background). A significant percentage of THRLBCL is refractory to RCHOP-based regimens and to CAR-T therapy; thus, the development of a specific therapeutic approach for these patients still represents an unmet clinical need. To better understand the interaction of immune cells in THRLBCL TME and identify more promising therapeutic strategies, we compared the immune gene expression profiles of 12 THRLBCL and 10 DLBCL samples, using the Nanostring PanCancer Immune Profiling panel. Gene co-expression network analysis identified the predominant role of the PD-1/PD-L1 axis in the modulation of the immune response. Furthermore, the PD-1/PD-L1 activation was flanked by the overexpression of as many as 48 genes related to the functional exhaustion of T-cells. Globally, THRLBCL TME was highly interferon-inflamed and severely exhausted. The immune gene profiling findings strongly candidate THRLBCL for anti-PD-1 therapy, but also allowed us to take a step forward in understanding THRLBCL TME. Of therapeutic relevance, we identified a subset of TCF1+ progenitor exhausted T-cells enriched in THRLBCL patients. This subset of TCF1+ exhausted T-cells correlates with good clinical response to immune checkpoint therapy and may improve prediction of anti-PD-1 response in THRLBCL patients.
2022-11-09 | GSE205919 | GEO
Project description:T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare and aggressive variant of diffuse large B-cell lymphoma (DLBCL) that usually affects young to middle-aged patients, with disseminated disease at presentation. The tumor microenvironment (TME) plays a key role in THRLBCL due to its peculiar cellular composition (<10% neoplastic B cells interspersed in a cytotoxic T-cell/histiocyte-rich background). A significant percentage of THRLBCL is refractory to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-based regimens and to chimeric antigen receptor T-cell therapy; thus, the development of a specific therapeutic approach for these patients represents an unmet clinical need. To better understand the interaction of immune cells in THRLBCL TME and identify more promising therapeutic strategies, we compared the immune gene expression profiles of 12 THRLBCL and 10 DLBCL samples, and further corroborated our findings in an extended in silico set. Gene coexpression network analysis identified the predominant role of the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis in the modulation of the immune response. Furthermore, the PD-1/PD-L1 activation was flanked by the overexpression of 48 genes related to the functional exhaustion of T cells. Globally, THRLBCL TME was highly interferon-inflamed and severely exhausted. The immune gene profiling findings strongly suggest that THRLBCL may be responsive to anti-PD-1 therapy but also allowed us to take a step forward in understanding THRLBCL TME. Of therapeutic relevance, we validated our results by immunohistochemistry, identifying a subset of TCF1+ (T cell-specific transcription factor 1, encoded by the TCF7 gene) progenitor exhausted T cells enriched in patients with THRLBCL. This subset of TCF1+ exhausted T cells correlates with good clinical response to immune checkpoint therapy and may improve prediction of anti-PD-1 response in patients with THRLBCL.
| S-EPMC9636403 | biostudies-literature
Project description:The goal of this study is to determine the capacity of Tcf1 to reprogram exhausted CD8+ T cells for function restoration. Tex cells elicited by chronic infection contain a CXCR5+Tim3– subset that has stem cell-like self-renewing capacity and expresses an elevated level of Tcf1 (termed Tex-stem), and Tex-stem cells depend on Tcf1 for generation and persistence. We show that ectopic Tcf1 expression profoundly affected the transcriptome of Tex cells.
2020-04-30 | GSE139057 | GEO
Project description:The goal of this study is to determine the capacity of Tcf1 to reprogram exhausted CD8+ T cells for function restoration. Tex cells elicited by chronic infection contain a CXCR5+Tim3– subset that has stem cell-like self-renewing capacity and expresses an elevated level of Tcf1 (termed Tex-stem), and Tex-stem cells depend on Tcf1 for generation and persistence. We show that ectopic Tcf1 expression profoundly affected the chromatin accessibility of Tex cells.
2020-04-30 | GSE139024 | GEO
Project description:Chronic viral infections are characterized by a state of CD8 T cell dysfunction termed exhaustion. A better understanding of the mechanisms that regulate CD8 T cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8 T cells. Here we identify a novel population of virus-specific CD8 T cells with a T follicular helper (Tfh)-like signature in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These Tfh-like CD8 T cells expressed the programmed cell death-1 (PD-1) inhibitory receptor but at the same time also expressed co-stimulatory molecules and had a gene signature that was related to CD8 T cell memory precursor cells and hematopoietic stem cells (HSC). These Tfh-like CD8 T cells acted as stem cells during chronic infection undergoing self-renewal and also differentiating into the terminally exhausted CD8 T cells that were present in both lymphoid and non-lymphoid tissues. The Tfh-like CD8 T cells were found only in lymphoid tissues and resided predominantly in the T cell zones along with naïve CD8 T cells. Interestingly, the proliferative burst after PD-1 blockade came almost exclusively from this Tfh-like CD8 T cell subset. Importantly, the transcription factor TCF1 played a cell intrinsic and essential role in the generation of Tfh-like CD8 T cells. Taken together, our study identifies Tfh-like CD8 T cells as the critical subset for maintaining the pool of virus-specific CD8 T cells during chronic infection and as the cells that proliferate after PD-1 blockade. These findings provide a better understanding of T cell exhaustion and have implications towards optimizing PD-1 directed immunotherapy. 8 samples isolated from CD8 T-cells in LCMV clone 13 GK1.5 infected mice (2 naïve, 3 CXCR5+Tim3-, 3 CXCR5-Tim3+) cells were analyzed
2016-08-02 | E-GEOD-84105 | biostudies-arrayexpress
Project description:The goal of this study is to determine the capacity of Tcf1 to reprogram exhausted CD8+ T cells for function restoration. Tex cells elicited by chronic infection contain a CXCR5+Tim3– subset that has stem cell-like self-renewing capacity and expresses an elevated level of Tcf1 (termed Tex-stem), and Tex-stem cells depend on Tcf1 for generation and persistence. We show that ectopic Tcf1 expression profoundly affected the transcriptome and chromatin accessibility of Tex cells.
2020-04-30 | GSE139056 | GEO
Project description:We have recently defined a novel population of PD-1+TCF1+virus-specific CD8 T cells that function as resource cells during chronic LCMV infection and provide the proliferative burst seen after PD-1 blockade. Such CD8 T cells have been found in other chronic infections and also in cancer in mice and humans. These CD8 T cells exhibit stem-like properties undergoing self-renewal and also giving rise to the terminally differentiated (exhausted) CD8 T cells. Here we compared the epigenetic signature of stem-like CD8 T cells with exhausted CD8 T cells. ATAC-seq analysis showed that stem-like CD8 T cells had a unique signature implicating activity of TCF (HMG family) and NF-κB (RHD family) members. In addition, transcription factor networks including Tcf7, Id3, and Bach2 were enriched in stem-like CD8 T cells. In contrast,exhausted CD8 T cells enriched accessible sites for ETS and Runx motifs in addition to a network encompassing Prdm1 and Il10. We also compared the epigenetic signatures of the two CD8 T-cellsubsets from chronically infected mice with effector and memory CD8 T cells generated after an acute LCMV infection. Both CD8T-cell subsets generated during chronic infection were strikingly different from CD8 T-cell subsets from acute infection. Interestingly, the stem-like CD8 T-cell subset from chronic infection, despite sharing key functional properties with memory CD8 T cells,had a very distinct epigenetic program. These results show that the chronic stem-like CD8 T-cell program represents a specific adaptation of the T-cell response to persistent antigenic stimulation.
2019-06-15 | GSE132110 | GEO
Project description:PD-1 blockade is important in treating progressive colorectal cancer (CRC). However, some patients with CRC have a poor or no response to immunotherapy. An important reason for this problem is the exhaustion of CD8+ T cells in the tumor microenvironment. Acetylcysteine (NAC) can reduce CD8+ T cell exhaustion in vitro and induce their differentiation into long-lasting phenotypes, thus enhancing the anti-tumor effect of adoptive T cell transfer. However, whether NAC can be combined with PD-1 blockade in CRC treatment and how NAC regulates CD8+ T cell differentiation remains unclear. We constructed a mouse CRC model to study the effect of NAC on tumors. The effect of NAC on CD8+ T cell differentiation and its potential mechanism were explored by cell flow assay and other studies in vitro and ex vivo. We demonstrated that NAC synergized PD-1 antibodies to inhibit CRC progression in a mouse CRC model, mediated by CD8+ T cells. NAC induces TCF1+PD1+CD8+ T cell differentiation and reduces the formation of exhausted T cells (Tex). Moreover, NAC enhanced the expression of Glut4 in CD8+ T cells, promoting the differentiation of TCF1+PD1+CD8+ T cells. Our study provides a novel idea for immunotherapy of clinically progressive CRC and suggests that Glut4 may be a new immunometabolic molecular target for regulating CD8+ T cell differentiation.
2024-05-23 | GSE252358 | GEO
Project description:T cell exhaustion is a state of CD8+ T cell dysfunction elicited by chronic exposure to antigen and inflammation, arises in both cancer and chronic viral infection. The co-inhibitory receptor PD-1 plays a key role in mediating exhaustion, but complete ablation of PD-1 by gene knock-out leads to deeper functional deficits and poor T cell survival. We hypothesized that an intermediate level of PD-1 expression may confer an improved balance of exhausted CD8+ T cell functionality, so we deleted an exhaustion-associated enhancer of PD-1 which indeed resulted in a reduced expression level. We compared EnhDel, WT and PD-1 KO T cells using single-cell RNA-Seq and found that PD-1 KO but not EnhDel cells are strongly biased towards the terminally exhausted subset. EnhDel cells also uniquely enrich for effector-associated genes and gene signatures. However, all three genotypes (EnhDel, WT and PD-1 KO) exhibit a similar chromatin accessibility landscape by ATAC-Seq, controlling for exhausted subset. These data suggest that tuning of PD-1 expression may uniquely permit the maintenance of an “effector” transcriptional profile in exhausted CD8+ T cells.
2024-07-29 | GSE269580 | GEO
Project description:T cell exhaustion is a state of CD8+ T cell dysfunction elicited by chronic exposure to antigen and inflammation, arises in both cancer and chronic viral infection. The co-inhibitory receptor PD-1 plays a key role in mediating exhaustion, but complete ablation of PD-1 by gene knock-out leads to deeper functional deficits and poor T cell survival. We hypothesized that an intermediate level of PD-1 expression may confer an improved balance of exhausted CD8+ T cell functionality, so we deleted an exhaustion-associated enhancer of PD-1 which indeed resulted in a reduced expression level. We compared EnhDel, WT and PD-1 KO T cells using single-cell RNA-Seq and found that PD-1 KO but not EnhDel cells are strongly biased towards the terminally exhausted subset. EnhDel cells also uniquely enrich for effector-associated genes and gene signatures. However, all three genotypes (EnhDel, WT and PD-1 KO) exhibit a similar chromatin accessibility landscape by ATAC-Seq, controlling for exhausted subset. These data suggest that tuning of PD-1 expression may uniquely permit the maintenance of an “effector” transcriptional profile in exhausted CD8+ T cells.
2024-07-29 | GSE212506 | GEO