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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 lose TEMRA in patients with leukemia relapse post transplant. Distribution of TN, TCM, TEM and TEMRA in T cells gated on each fraction of cells based on PD-1 and TIM-3 expression from relapse patients. (a) Representative dot plots from one relapse patient (09). (b) Summary data for five relapse patients (08, 09, 10, 11 and 12).
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fig5: PD-1hiTIM3+ cells lose TEMRA in patients with leukemia relapse post transplant. Distribution of TN, TCM, TEM and TEMRA in T cells gated on each fraction of cells based on PD-1 and TIM-3 expression from relapse patients. (a) Representative dot plots from one relapse patient (09). (b) Summary data for five relapse patients (08, 09, 10, 11 and 12).

Mentions: Based on the expression of CD45RA and CCR7, T cells are generally divided into four subsets: naive T cells (TN, CCR7+CD45RA+), central memory T cells (TCM, CCR7+CD45RA-), effector memory T cells (TEM, CCR7-CD45RA−) and terminally differentiated effector cells (TEMRA, CCR7-CD45RA+).33, 34 By multichannel flow cytometry, we examined the distribution of all these four subsets among PD-1hiTIM-3+ T cells (fraction VI) as well as other T-cell fractions (fractions I–V) based on PD-1 and TIM-3 expression. In contrast to other fractions that mostly consist of all four T-cell subsets, PD-1hiTIM-3+ T cells are clearly antigen experienced as they had entirely lost the TN subset. The majority of PD-1hiTIM-3+ cells are TCM or TEM. Interestingly, TEMRA also are significantly decreased in this cell fraction. This occurred in both CD4+ and CD8+ T cells from leukemia relapse patients (Figure 5). Similar patterns of expression were observed in patients maintained in remission (Supplementary Figure 1). Of note, fraction III (PD-1hiTIM-3−) cells are phenotypically shifted toward the stage of PD-1hiTIM-3+ cells by loss of the TN subset and minimal accumulation of the TEMRA subset. We performed functional analysis to evaluate cytokine release of each T-cell subset using cells from one relapse patient (patient 11). TEMRA play a dominant role in producing TNF-α and IFN-γ in both CD4+ and CD8+ T cells (Supplementary Figure 2). Thus, loss of TEMRA might contribute to the functional defect of PD-1hiTIM-3+ T cells. Taken together, these results support that PD-1hiTIM-3+ cells are phenotypically antigen-experienced T cells that have lost functional subsets, consistent with a state of T-cell exhaustion.


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 lose TEMRA in patients with leukemia relapse post transplant. Distribution of TN, TCM, TEM and TEMRA in T cells gated on each fraction of cells based on PD-1 and TIM-3 expression from relapse patients. (a) Representative dot plots from one relapse patient (09). (b) Summary data for five relapse patients (08, 09, 10, 11 and 12).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: PD-1hiTIM3+ cells lose TEMRA in patients with leukemia relapse post transplant. Distribution of TN, TCM, TEM and TEMRA in T cells gated on each fraction of cells based on PD-1 and TIM-3 expression from relapse patients. (a) Representative dot plots from one relapse patient (09). (b) Summary data for five relapse patients (08, 09, 10, 11 and 12).
Mentions: Based on the expression of CD45RA and CCR7, T cells are generally divided into four subsets: naive T cells (TN, CCR7+CD45RA+), central memory T cells (TCM, CCR7+CD45RA-), effector memory T cells (TEM, CCR7-CD45RA−) and terminally differentiated effector cells (TEMRA, CCR7-CD45RA+).33, 34 By multichannel flow cytometry, we examined the distribution of all these four subsets among PD-1hiTIM-3+ T cells (fraction VI) as well as other T-cell fractions (fractions I–V) based on PD-1 and TIM-3 expression. In contrast to other fractions that mostly consist of all four T-cell subsets, PD-1hiTIM-3+ T cells are clearly antigen experienced as they had entirely lost the TN subset. The majority of PD-1hiTIM-3+ cells are TCM or TEM. Interestingly, TEMRA also are significantly decreased in this cell fraction. This occurred in both CD4+ and CD8+ T cells from leukemia relapse patients (Figure 5). Similar patterns of expression were observed in patients maintained in remission (Supplementary Figure 1). Of note, fraction III (PD-1hiTIM-3−) cells are phenotypically shifted toward the stage of PD-1hiTIM-3+ cells by loss of the TN subset and minimal accumulation of the TEMRA subset. We performed functional analysis to evaluate cytokine release of each T-cell subset using cells from one relapse patient (patient 11). TEMRA play a dominant role in producing TNF-α and IFN-γ in both CD4+ and CD8+ T cells (Supplementary Figure 2). Thus, loss of TEMRA might contribute to the functional defect of PD-1hiTIM-3+ T cells. Taken together, these results support that PD-1hiTIM-3+ cells are phenotypically antigen-experienced T cells that have lost functional subsets, consistent with a state of T-cell exhaustion.

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