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PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation.

Kong Y, Zhang J, Claxton DF, Ehmann WC, Rybka WB, Zhu L, Zeng H, Schell TD, Zheng H - Blood Cancer J (2015)

Bottom Line: T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3).Consistent with exhaustion, PD-1(hi)TIM-3(+) T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ).In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing TN and TEMRA subsets.

View Article: PubMed Central - PubMed

Affiliation: 1] Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA [2] Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.

ABSTRACT
Prognosis of leukemia relapse post allogeneic stem cell transplantation (alloSCT) is poor and effective new treatments are urgently needed. T cells are pivotal in eradicating leukemia through a graft versus leukemia (GVL) effect and leukemia relapse is considered a failure of GVL. T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3). To evaluate whether T-cell exhaustion and inhibitory pathways are involved in leukemia relapse post alloSCT, we performed phenotypic and functional studies on T cells from peripheral blood of acute myeloid leukemia patients receiving alloSCT. Here we report that PD-1(hi)TIM-3(+) cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1(hi)TIM-3(+) T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing TN and TEMRA subsets. Importantly, increase of PD-1(hi)TIM-3(+) cells occurs before clinical diagnosis of leukemia relapse, suggesting their predictive value. Results of our study provide an early diagnostic approach and a therapeutic target for leukemia relapse post transplantation.

No MeSH data available.


Related in: MedlinePlus

Expression of PD-1 and TIM3 is enhanced on T cells from patients with leukemia relapse post transplant. Flow cytometry analysis of surface expression of BTLA, 2B4, LAG3, CD160, TIM-3 and PD-1 was performed on PBMCs collected from AML patients post alloSCT. (a–g) Histogram displays the expression of above receptors on T cells from representative patients of relapse vs remission. CD4+ or CD8+ cells were gated. Percentage of cells expressing each receptor is shown. Panels on right are plots of expression of each receptor on CD4+ or CD8+ T cells from patients with relapse (n=4–5) vs remission (n=6). Each square represents data from one patient. **P<0.01.
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fig1: Expression of PD-1 and TIM3 is enhanced on T cells from patients with leukemia relapse post transplant. Flow cytometry analysis of surface expression of BTLA, 2B4, LAG3, CD160, TIM-3 and PD-1 was performed on PBMCs collected from AML patients post alloSCT. (a–g) Histogram displays the expression of above receptors on T cells from representative patients of relapse vs remission. CD4+ or CD8+ cells were gated. Percentage of cells expressing each receptor is shown. Panels on right are plots of expression of each receptor on CD4+ or CD8+ T cells from patients with relapse (n=4–5) vs remission (n=6). Each square represents data from one patient. **P<0.01.

Mentions: It has been reported that several receptors including BTLA, 2B4, LAG-3, CD160, TIM-3 and PD-1 are upregulated on the T-cell surface to mediate T-cell exhaustion in a variety of tumors.18 To determine whether these exhaustion markers associate with AML relapse post transplantation, we performed flow cytometric analysis of these molecules using PBMCs from 11 patients post alloSCT, among whom 5 had leukemia relapse whereas the other 6 remained in remission at the time of sample collection. Table 1 outlines the patients' clinical characteristics. Expressions of BTLA, 2B4, LAG-3 and CD160 were comparable between relapse and remission patients (Figures 1a–d), whereas the percentage of TIM-3+ cells among CD8+ T cells was significantly higher in patients who had leukemia relapse (P=0.0051; Figure 1e). CD4+ T cells showed a similar trend but did not achieve statistical significance (P=0.1684; Figure 1e). Importantly, although the percentage of overall PD-1+ cells showed no difference (Figure 1f), we consistently detected an increase in the proportion of cells expressing high levels of PD-1 (PD-1hi). Consistent with TIM-3 data, PD-1hi CD8+ T cells were more predominant in relapse patients compared with remission patients (P=0.0025; Figure 1g). CD4+ T cells showed the same trend, although not statistically significant (P=0.1359; Figure 1g). These data suggest a role for TIM-3 and PD-1 in leukemia relapse post alloSCT.


PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation.

Kong Y, Zhang J, Claxton DF, Ehmann WC, Rybka WB, Zhu L, Zeng H, Schell TD, Zheng H - Blood Cancer J (2015)

Expression of PD-1 and TIM3 is enhanced on T cells from patients with leukemia relapse post transplant. Flow cytometry analysis of surface expression of BTLA, 2B4, LAG3, CD160, TIM-3 and PD-1 was performed on PBMCs collected from AML patients post alloSCT. (a–g) Histogram displays the expression of above receptors on T cells from representative patients of relapse vs remission. CD4+ or CD8+ cells were gated. Percentage of cells expressing each receptor is shown. Panels on right are plots of expression of each receptor on CD4+ or CD8+ T cells from patients with relapse (n=4–5) vs remission (n=6). Each square represents data from one patient. **P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526784&req=5

fig1: Expression of PD-1 and TIM3 is enhanced on T cells from patients with leukemia relapse post transplant. Flow cytometry analysis of surface expression of BTLA, 2B4, LAG3, CD160, TIM-3 and PD-1 was performed on PBMCs collected from AML patients post alloSCT. (a–g) Histogram displays the expression of above receptors on T cells from representative patients of relapse vs remission. CD4+ or CD8+ cells were gated. Percentage of cells expressing each receptor is shown. Panels on right are plots of expression of each receptor on CD4+ or CD8+ T cells from patients with relapse (n=4–5) vs remission (n=6). Each square represents data from one patient. **P<0.01.
Mentions: It has been reported that several receptors including BTLA, 2B4, LAG-3, CD160, TIM-3 and PD-1 are upregulated on the T-cell surface to mediate T-cell exhaustion in a variety of tumors.18 To determine whether these exhaustion markers associate with AML relapse post transplantation, we performed flow cytometric analysis of these molecules using PBMCs from 11 patients post alloSCT, among whom 5 had leukemia relapse whereas the other 6 remained in remission at the time of sample collection. Table 1 outlines the patients' clinical characteristics. Expressions of BTLA, 2B4, LAG-3 and CD160 were comparable between relapse and remission patients (Figures 1a–d), whereas the percentage of TIM-3+ cells among CD8+ T cells was significantly higher in patients who had leukemia relapse (P=0.0051; Figure 1e). CD4+ T cells showed a similar trend but did not achieve statistical significance (P=0.1684; Figure 1e). Importantly, although the percentage of overall PD-1+ cells showed no difference (Figure 1f), we consistently detected an increase in the proportion of cells expressing high levels of PD-1 (PD-1hi). Consistent with TIM-3 data, PD-1hi CD8+ T cells were more predominant in relapse patients compared with remission patients (P=0.0025; Figure 1g). CD4+ T cells showed the same trend, although not statistically significant (P=0.1359; Figure 1g). These data suggest a role for TIM-3 and PD-1 in leukemia relapse post alloSCT.

Bottom Line: T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3).Consistent with exhaustion, PD-1(hi)TIM-3(+) T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ).In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing TN and TEMRA subsets.

View Article: PubMed Central - PubMed

Affiliation: 1] Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA [2] Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.

ABSTRACT
Prognosis of leukemia relapse post allogeneic stem cell transplantation (alloSCT) is poor and effective new treatments are urgently needed. T cells are pivotal in eradicating leukemia through a graft versus leukemia (GVL) effect and leukemia relapse is considered a failure of GVL. T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3). To evaluate whether T-cell exhaustion and inhibitory pathways are involved in leukemia relapse post alloSCT, we performed phenotypic and functional studies on T cells from peripheral blood of acute myeloid leukemia patients receiving alloSCT. Here we report that PD-1(hi)TIM-3(+) cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1(hi)TIM-3(+) T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing TN and TEMRA subsets. Importantly, increase of PD-1(hi)TIM-3(+) cells occurs before clinical diagnosis of leukemia relapse, suggesting their predictive value. Results of our study provide an early diagnostic approach and a therapeutic target for leukemia relapse post transplantation.

No MeSH data available.


Related in: MedlinePlus