Limits...
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

Increase of PD-1hiTIM3+ cells predict leukemia relapse. PBMCs from a patient (08) who had leukemia relapse 5 month post alloSCT were collected at different time points post transplant. (a) Flow cytometry data of expression of PD-1hiTIM3+ cells among CD4+ or CD8+ T cells. (b) Plot of the percentage of PD-1hiTIM-3+ cells among CD4+ or CD8+ T cells kinetically post transplantation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4526784&req=5

fig6: Increase of PD-1hiTIM3+ cells predict leukemia relapse. PBMCs from a patient (08) who had leukemia relapse 5 month post alloSCT were collected at different time points post transplant. (a) Flow cytometry data of expression of PD-1hiTIM3+ cells among CD4+ or CD8+ T cells. (b) Plot of the percentage of PD-1hiTIM-3+ cells among CD4+ or CD8+ T cells kinetically post transplantation.

Mentions: To determine whether PD-1hiTIM-3+ T cells predict leukemia relapse in AML patients post alloSCT, we evaluated serial samples at 1, 3, 4, 5 (relapse point) and 6 months (achieved remission after reinduction chemotherapy) post transplantation. Cells were evaluated from patient 08 who received matched unrelated donor transplantation for high-risk AML. She was initially doing well until 5 month after transplantation when thrombocytopenia was noted and bone marrow biopsy confirmed leukemia relapse. She then received reinduction chemotherapy and was able to achieve a second complete remission. PBMCs were analyzed by flow cytometry for expression of PD-1 and TIM-3 on CD4+ and CD8+ T cells. As shown in Figure 6, the percentage of PD-1hiTIM-3+ T cells started to increase as early as 3 months post transplantation, which is 2 months before clinical diagnosis of relapse. It increased further at 4 months post transplantation and reached the highest level at 5 months, the time of clinical diagnosis of relapse. This pattern is consistent in both CD4+ and CD8+ T cells. Importantly the percentage of PD-1hiTIM-3+ T cells decreased at 6 month post transplantation, at which time this patient regained remission after a course of reinduction chemotherapy. In contrast, the percentage of PD-1hiTIM-3+ cells remained at low levels in patients maintained in remission post transplantation (Supplementary Figure 3). Thus, elevation of the percentage of PD-1hiTIM-3+T cells can be considered as a predictive biomarker for leukemia relapse post transplantation.


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)

Increase of PD-1hiTIM3+ cells predict leukemia relapse. PBMCs from a patient (08) who had leukemia relapse 5 month post alloSCT were collected at different time points post transplant. (a) Flow cytometry data of expression of PD-1hiTIM3+ cells among CD4+ or CD8+ T cells. (b) Plot of the percentage of PD-1hiTIM-3+ cells among CD4+ or CD8+ T cells kinetically post transplantation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig6: Increase of PD-1hiTIM3+ cells predict leukemia relapse. PBMCs from a patient (08) who had leukemia relapse 5 month post alloSCT were collected at different time points post transplant. (a) Flow cytometry data of expression of PD-1hiTIM3+ cells among CD4+ or CD8+ T cells. (b) Plot of the percentage of PD-1hiTIM-3+ cells among CD4+ or CD8+ T cells kinetically post transplantation.
Mentions: To determine whether PD-1hiTIM-3+ T cells predict leukemia relapse in AML patients post alloSCT, we evaluated serial samples at 1, 3, 4, 5 (relapse point) and 6 months (achieved remission after reinduction chemotherapy) post transplantation. Cells were evaluated from patient 08 who received matched unrelated donor transplantation for high-risk AML. She was initially doing well until 5 month after transplantation when thrombocytopenia was noted and bone marrow biopsy confirmed leukemia relapse. She then received reinduction chemotherapy and was able to achieve a second complete remission. PBMCs were analyzed by flow cytometry for expression of PD-1 and TIM-3 on CD4+ and CD8+ T cells. As shown in Figure 6, the percentage of PD-1hiTIM-3+ T cells started to increase as early as 3 months post transplantation, which is 2 months before clinical diagnosis of relapse. It increased further at 4 months post transplantation and reached the highest level at 5 months, the time of clinical diagnosis of relapse. This pattern is consistent in both CD4+ and CD8+ T cells. Importantly the percentage of PD-1hiTIM-3+ T cells decreased at 6 month post transplantation, at which time this patient regained remission after a course of reinduction chemotherapy. In contrast, the percentage of PD-1hiTIM-3+ cells remained at low levels in patients maintained in remission post transplantation (Supplementary Figure 3). Thus, elevation of the percentage of PD-1hiTIM-3+T cells can be considered as a predictive biomarker for leukemia relapse post transplantation.

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