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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

PD-1hiTIM3+ cells associate with leukemia relapse post alloSCT. PBMCs from patients with leukemia relapse vs remission were tested for PD-1 and TIM3 expression on CD4+ and CD8+ T cells by flow cytometry. (a) Based on levels of PD-1 and TIM3 expression, cells are divided into six fractions. Shown is the schema of each fraction. (b) Representative flow data from one relapse (patient 09) and one remission (patient 02). Percentage of PD-1hiTIM-3+ among CD4+ or CD8+ cells is shown. (c) Plot of percentage of each fraction among CD4+ or CD8+ cells in patient with relapse (n=5) vs remission (n=6). Each square represents data of an individual patient. *P<0.05, **P<0.01.
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fig2: PD-1hiTIM3+ cells associate with leukemia relapse post alloSCT. PBMCs from patients with leukemia relapse vs remission were tested for PD-1 and TIM3 expression on CD4+ and CD8+ T cells by flow cytometry. (a) Based on levels of PD-1 and TIM3 expression, cells are divided into six fractions. Shown is the schema of each fraction. (b) Representative flow data from one relapse (patient 09) and one remission (patient 02). Percentage of PD-1hiTIM-3+ among CD4+ or CD8+ cells is shown. (c) Plot of percentage of each fraction among CD4+ or CD8+ cells in patient with relapse (n=5) vs remission (n=6). Each square represents data of an individual patient. *P<0.05, **P<0.01.

Mentions: We further dissected the association between expression of PD-1 and TIM-3 with leukemia relapse. Based on the level of PD-1 vs TIM-3, both CD4+ and CD8+ T cells can be divided into six subpopulations as shown in Figure 2a. Critically, we detected significantly higher frequencies of PD-1hiTIM-3+ (fraction VI) cells in samples from patients with leukemia relapse compared with that of patients who remained in remission. The median frequencies of CD8+ T cells expressing PD-1hi TIM-3+ were 8.6%, compared with 0.5% in patients maintaining remission (P=0.0022; Figures 2b and c). This phenomenon occurred in CD4+ T cells as well (P=0.0496; Figures 2b and c). Fraction III (PD-1hiTIM-3−) and fraction V (PD-1medTIM-3+) showed a pattern similar to fraction VI, but only CD8+ T cells exhibited statistical significances (P=0.0155 and 0.0429 for fraction III and V, respectively; Figures 2b and c). This is an important finding suggesting that PD-1hiTIM-3+ T cells are associated with 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)

PD-1hiTIM3+ cells associate with leukemia relapse post alloSCT. PBMCs from patients with leukemia relapse vs remission were tested for PD-1 and TIM3 expression on CD4+ and CD8+ T cells by flow cytometry. (a) Based on levels of PD-1 and TIM3 expression, cells are divided into six fractions. Shown is the schema of each fraction. (b) Representative flow data from one relapse (patient 09) and one remission (patient 02). Percentage of PD-1hiTIM-3+ among CD4+ or CD8+ cells is shown. (c) Plot of percentage of each fraction among CD4+ or CD8+ cells in patient with relapse (n=5) vs remission (n=6). Each square represents data of an individual patient. *P<0.05, **P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: PD-1hiTIM3+ cells associate with leukemia relapse post alloSCT. PBMCs from patients with leukemia relapse vs remission were tested for PD-1 and TIM3 expression on CD4+ and CD8+ T cells by flow cytometry. (a) Based on levels of PD-1 and TIM3 expression, cells are divided into six fractions. Shown is the schema of each fraction. (b) Representative flow data from one relapse (patient 09) and one remission (patient 02). Percentage of PD-1hiTIM-3+ among CD4+ or CD8+ cells is shown. (c) Plot of percentage of each fraction among CD4+ or CD8+ cells in patient with relapse (n=5) vs remission (n=6). Each square represents data of an individual patient. *P<0.05, **P<0.01.
Mentions: We further dissected the association between expression of PD-1 and TIM-3 with leukemia relapse. Based on the level of PD-1 vs TIM-3, both CD4+ and CD8+ T cells can be divided into six subpopulations as shown in Figure 2a. Critically, we detected significantly higher frequencies of PD-1hiTIM-3+ (fraction VI) cells in samples from patients with leukemia relapse compared with that of patients who remained in remission. The median frequencies of CD8+ T cells expressing PD-1hi TIM-3+ were 8.6%, compared with 0.5% in patients maintaining remission (P=0.0022; Figures 2b and c). This phenomenon occurred in CD4+ T cells as well (P=0.0496; Figures 2b and c). Fraction III (PD-1hiTIM-3−) and fraction V (PD-1medTIM-3+) showed a pattern similar to fraction VI, but only CD8+ T cells exhibited statistical significances (P=0.0155 and 0.0429 for fraction III and V, respectively; Figures 2b and c). This is an important finding suggesting that PD-1hiTIM-3+ T cells are associated with 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