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Predictive Role of Circulating Immune Cell Subtypes Early after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Leukemia
International Journal of Stem Cells 2019;12:73-83
Published online March 30, 2019;  
© 2019 Korean Society for Stem Cell Research.

Tae Woo Kim1, Sung-Soo Park1, Ji-Young Lim1, Gi June Min1, Silvia Park1, Young-Woo Jeon1,2, Seung-Ah Yahng3, Seung-Hwan Shin4, Sung-Eun Lee1,2, Jae-Ho Yoon1,2, Byung-Sik Cho1,2, Ki-Seong Eom1,2, Seok Lee1,2, Hee-Je Kim1,2, Chang-Ki Min1,2

1Department of Hematology, Seoul St. Mary’s Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea, 2Leukemia Research Institute, The Catholic University of Korea, Seoul, Korea, 3Department of Hematology, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea, 4Department of Hematology, Yeoido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
Correspondence to: Chang-Ki Min, Department of Hematology, St. Mary’s Hematology Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea, Tel: +82-2-2258-6054, Fax: +82-2-599-3589, E-mail: ckmin@catholic.ac.kr
Received October 15, 2018; Revised October 15, 2018; Accepted November 9, 2018.
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Background and Objectives

Cells of innate immunity normally recover in the first weeks to months after allogenenic hematopoietic stem cell transplantation (allo-HSCT). Their relevance in terms of graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect is largely unknown. The predictive role of early recovery in the immune cells on acute GVHD and GVL effect after allo-HSCT was investigated in patients with acute leukemia who achieved the first complete remission.

Methods

Peripheral blood samples were taken at the median of 14 days (range, 12~29 days) after allo-HSCT. A cohort including 119 samples and characteristics of patients were analyzed. Immune cell populations were identified by flow cytometry.

Results

The median age was 49.0 years (range, 21~69) at transplantation. Univariate analysis showed that age less than 40 years old, lower frequencies of CD8+ T cells, invariant natural killer T (iNKT) cells, monocytic myeloid derived suppressor cells (M-MDSCs) and higher frequency of immature MDSCs were associated with occurrence of grade III–IV acute GVHD. Multivariate analyses showed that iNKT cells (hazard ratio (HR), 0.453, 95% CI, 0.091~0.844, p=0.024) and M-MDSCs (HR, 0.271, 95% CI, 0.078~0.937, p=0.039) were independent factors. Combination of higher frequencies of both cell subsets was associated with lower incidence of grade III–IV acute GVHD, whereas patients with lower frequency of iNKT cells and higher frequency of M-MDSCs showed significant higher probability of relapse.

Conclusions

iNKT cells and M-MDSCs could be relevant cell biomarkers for predicting acute GVHD and/or relapse in acute leukemia patients treated with allo-HSCT.

Keywords : Invariant NKT cells, Myeloid-derived suppressor cells, Acute leukemia, Graft-versus-host disease, Graft-versus-leukemia effect, Allogeneic hematopoietic stem cell transplantation
Results

Patients’ characteristics

The median age of patients at HSCT was 49.0 years (range, 21 to 69 years). We identified 74 (62.2%) of AML, 44 (37.8%) of ALL, 1 (0.8%) of mixed phenotype of acute leukemia. Stem cells were collected from 48 (40.3%) of matched sibling, 40 (33.6%) of unrelated, 23 (19.3%) of haploidentical related, and 8 (7.6%) of double cord donor. Except for HSCT using double cord blood, donor source included 93 (78.2%) of peripheral blood and 18 (15.1%) of bone marrow. ATG was administered in 77 (64.7%) patients with median dose of 2.5 mg/kg (range, 1.25~10 mg/kg). Regarding post-transplant immune populations, median frequencies of CD8+ T cells, iNKT cells, I-MDSCs, and M-MDSCs per MNCs were observed as 14.3% (range, 0.002~54.0), 0.061% (range, 0.0~8.805), 0.258% (range, 0.009~13.4) and 0.109% (range, 0.004~4.325), respectively. Other data of clinical characteristics and post-transplant immune cell populations are summarized in Table 1.

Survival and acute GVHD outcomes

After a median follow-up of 9.2 months (range, 1.2~24.9 months) for survivors, estimated OS and DFS rates at 1 years were 87.3% (95% CI, 78.5~92.7) and 83.8% (95% CI, 74.6~89.9), respectively. One-year cumulative incidences of relapse and TRM were 8.7% (95% CI, 4.2~15.4) and 7.4% (95% CI, 3.2~14.1), respectively (Supplementary Fig. 2). 180-day cumulative incidences of grades II~IV and grade III~IV acute GVHD were 35.4% (95% CI, 26.8~44.0) and 10.9% (95% CI, 6.1~17.3), respectively (Supplementary Fig. 3).

Predictive factors for acute GVHD

Univariate analysis showed that age less than 40 years old (p=0.077), lower frequencies of post-HSCT CD8+ T cells (≤5.8% per MNC), iNKT cells (≤0.027% per MNC), and M-MDSCs (≤0.27% per MNC), and higher frequency of I-MDSCs (>0.11% per MNC) were potential factors that increase the incidence of grade III~IV acute GVHD (Supplementary Table 1). Multivariate analyses showed that only post-HSCT iNKT cells (hazard ratio (HR), 0.453, 95% CI, 0.091~0.844, p=0.024) and post-HSCT M-MDSCs (HR, 0.271, 95% CI, 0.078~0.937, p=0.039) were independent factors affecting the incidence of grade III~IV acute GVHD (Table 2). The factor of donor type was intentionally included in multivariate analysis regardless of p value in univariate analysis. It did not affect incidence of grade III~IV acute GVHD. We analyzed the additional factors causing the changes in iNKT cells and M-MDSCs in Supplementary Table 2. No other factors among post-HSCT immune cells were identified that affected grade II~IV acute GVHD (data not shown).

Impact of post-HSCT iNKT cells and M-MDSCs on survival outcomes and acute GVHD

Effect of the two immune cell populations that were critical for grade III~IV acute GVHD on conventional transplant outcomes was assessed (Table 3). Apart from significant impacts of post-HSCT iNKT cells and M-MDSCs on grade III~IV acute GVHD, either lower frequency of iNKT cells or higher frequency of M-MDSCs had a trend of higher probability of relapse (for iNKT cells, 13.0% vs. 0.7%, p=0.08; for M-MDSCs, 3.5% vs. 13.8%, p=0.059). Except for incidence of relapse, the two subtypes of immune cells did not significantly affect the other survival outcomes including OS, DFS, and incidence of TRM.

Next, we analyzed impact of combination of post-transplant iNKT cells and M-MDSCs on grade III~IV acute GVHD and survival outcomes. Combination of higher frequencies of iNKT cells and M-MDSCs was associated with lower incidence of grade III~IV acute GVHD compared to those of lower frequencies of iNKT cells and M-MDSCs [2.8% (95% CI, 0.2~12.6) vs. 31.6% (95% CI, 12.4~52.9), p=0.002] (Fig. 1). Whereas any combination did not show significant impact on OS (p=0.696), DFS (p=0.418), or incidence of TRM (p=0.282) (Fig. 2A, B, D), the combination with lower frequency of iNKT cell and higher frequency of M-MDSCs showed significant higher probability of relapse compared to those with higher frequency of iNKT cell and lower frequency of M-MDSCs [20.9% (95% CI, 12.4~52.9) vs. 2.9% (95% CI, 0.2~12.6), p= 0.011] (Fig. 2C).

Discussion

We showed that two immune cell populations, iNKT cells and M-MDSCs, expanded shortly after clinical allo-HSCT were associated with grade III~IV acute GVHD and leukemia relapse. Higher frequency of iNKT cells in the peripheral blood of the patients post-transplantation was associated with a reduction in acute GVHD risk, importantly with a trend in reduced leukemia relapse. And the recovery of circulating M-MDSCs also was more critical to reduced occurrence of acute GVHD but there was a trend in increased leukemia relapse. Patients with lower recovery of both iNKT cells and M-MDSCs had a significantly increased grade III~IV acute GVHD, whereas interestingly the combination of higher iNKT cells and lower M-MDSCs correlated with increase enhancement of GVL effect after allo-HSCT. Therefore, potency of iNKT cells after allo-HSCT is likely to be dependent on the expansion of M-MDSCs in the context to the regulation of GVHD and GVL effec. iNKT cells are a rare subset of T lymphocytes which are characterized by the coexpression of NK and T cell markers. They express a T cell receptor (TCR) which is semi-invariant (Vα24Jα18 typically pairing with Vβ11 in humans) and which recognizes glycolipid antigens presented by the non-polymorphic MHC Class I-like molecule CD1d with high affinity (23). Despite their rarity, iNKT cells exert potent immunomodulatory functions bridging the innate and adaptive immune systems by rapidly producing large amounts of cytokines and chemokines. This results either in enhanced immune responses (i.e., defense against pathogens, immunosurveillance in cancer) via the production of Th1 cytokines such as interferon (IFN)-γ or in suppression of autoimmune and alloimmune reactions by the production of interleukin (IL)-4 and IL-10 (24, 25). First human report delineating iNKT reconstitution following allo-HSCT demonstrated a correlation between increased peripheral blood iNKT cell count and reduced acute and chronic GVHD (26). Early post-transplantation iNKT recovery such as iNKT/T ratio at day 15 predicted acute GVHD and OS (27). It has been reported that recovery of iNKT cells is also associated with enhanced GVL effect (28, 29), suggesting that monitoring of iNKT cell reconstitution post-transplant and adoptively transferring donor iNKT cells may be a method by which relapse could be prevented (30).

MDSCs, morphologically a mixture of monocytic and granulocytic cells, accumulate in large numbers during many pathologic conditions, including cancer, infectious diseases, trauma, or sepsis. They are characterized by their myeloid origin, immature state, and most importantly by their potent ability to suppress different aspects of immune responses, especially T-cell proliferation and cytokine production (31). We previously showed that two main subgroups of MDSCs differentially expanded shortly after clinical allo-HSCT and increased expansion of M-MDSCs was more critical to the occurrence of early infections, 1-year TRM and lower survival (32).

In this study, we demonstrate the possibility that circulating iNKT cells cooperate with M-MDSCs in protecting patients with acute leukemia against the development of grade III~IV acute GVHD and leukemia relapse after allo-HSCT. Several studies have proposed a link between iNKT cells and MDSCs. In mice, MDSC activation was dependent on the presence of host iNKT cells. The conditioning regimen polarized the host iNKT cells toward IL-4 secretion, and MDSC activation was dependent on IL-4 (33). NKT cell activation via glycolipid-loaded den-dritic cells decreased the frequency and immunosuppressive activity of MDSCs in tumor-resected mice. In vitro, NKT cells were resistant to the immunosuppressive effects of MDSCs and were able to reverse the inhibitory effects of MDSCs on T cell proliferation (34). iNKT cells have been shown to regulate MDSC-mediated immune suppression during viral infection (35), suggesting that the interaction between iNKT cells and M-MDSCs on leukemia-associated immunosuppression in the context of allo-HSCT requires further investigation.

We acknowledge that the single institution and measurements only at one point are inherent flaws of our study, although these limitations are mitigated to some degree by the relatively large size of the cohort. Our measurement time point was supported in analyses looking at the recovery of innate immunity over time, which both subsets of immune cells, iNKT cells and M-MDSCs maximally recovered between 2 and 4 weeks, well before the recovery of adaptive immunity (36). In the TCR α chain of human iNKT cells, the Vα24 segment is joined with Jα18 in a germ-line configuration, resulting in an invariant CDR3 loop encoded by the mature TCR α chain (37). This α chain pairs with a restricted range of randomly rearranged Vβ chains, with Vβ11 being the most prominent in humans (38). In our study, iNKT cells were identified with the expression of CD3, CD56 and antiTCRVβ11. Non-invariant and non-CD1d-restricted V α24+ T cells can also pair with Vβ11, and contribute to the Vα24+/Vβ11+ subpopulation. This could lead to an overestimation of iNKT cell number, especially in individuals with decreased number of iNKT cells. Of note, in our study significant change in TRM, DFS or OS was not noted in spite of reduced acute GVHD and leukemia relapse. Our observations should be interpreted with some caution until it is validated in a large independent cohort with long-term follow-up.

In summary, iNKT cells and M-MDSCs in peripheral blood early after transplantation can be attractive biomarkers to predict allo-HSCT outcomes including acute GVHD and leukemia relapse. Although rare in number, circulating iNKT cells and M-MDSCs may represent the most versatile and critical cell population for suppressing acute GVHD. In particular, iNKT cells can thus be harnessed to suppress undesirable allo-immune responses while maintaining desirable GVL effect together with reduced M-MDSCs.

Supplementary Information
Acknowledgments

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Walfare, Republic of Korea (#HI16C0047).

Figures
Fig. 1. Cumulative incidence of grade III–IV acute GVHD accoring to the combinations of frequency of invariant natural killer cells (iNKT) and monocytic myeloid-derived suppressor cell population (M-MDSC). Black line, lower iNKT (≤ 0.027%) + lower M-MDSC (≤ 0.27%), n=19; Red line, lower iNKT (≤ 0.027%) + higher M-MDSC (> 0.27%), n=20; Green line, higher iNKT (> 0.027%) + lower M-MDSC (≤ 0.27%), n=42; Blue line, higher iNKT (> 0.027%) + lower M-MDSC (> 0.27%), n=36.
Fig. 2. Major outcomes accoring to the combinations of frequency of invariant natural killer cells (iNKT) and monocytic myeloid-derived suppressor cell population (M-MDSC). Black line, lower iNKT (≤ 0.027%) + lower M-MDSC (≤ 0.27%), n=19; Red line, lower iNKT (≤ 0.027%) + higher M-MDSC (> 0.27%), n=20; Green line, higher iNKT (> 0.027%) + lower M-MDSC (≤ 0.27%), n=42; Blue line, higher iNKT (> 0.027%) + lower M-MDSC (> 0.27%), n=36. (A) Overall survival, (B) disease-free survival, (C) cumulative incidence of relaspse, and (D) cumualtive incidence of transplant-related mortality (TRM).
TABLES

Patient characteristics

VariablesTotal patient (N=119)
Median patient’s age at transplant, years (range)46 (21~69)
Median donor’s age, years (range)35 (14~63)
 Gender of patient, male (N, %)61 (51.3)
 Gender of donor, male (N, %)83 (69.7)
  Female to male transplant (N, %)19 (16.0)
  Not available to evaluate (heterogeneous sex in double cord donor) (N, %)5 (4.2)
Diagnosis
 Acute myeloid leukemia (N, %)74 (62.2)
 Acute lymphoblastic leukemia (N, %)44 (37.8)
 Mixed phenotype acute leukemia (N, %)1 (0.8)
Donor type
 HLA-well matched sibling (N, %)48 (40.3)
 HLA-well matched unrelated (N, %)37 (31.1)
 HLA-partial matched unrelated (N, %)3 (2.5)
 Haploidentical related (N, %)23 (19.3)
 Double cord (N, %)8 (7.6)
Donor source
 Peripheral blood93 (78.2)
 Bone marrow18 (15.1)
 Cord blood8 (6.7)
Comorbidity (HCT-CI*)
 Low to intermediate (score <3) (N, %)81 (68.1)
 High (score ≥3) (N, %)38 (31.9)
Conditioning intensity
 Myeloablative conditioning (N, %)84 (70.6)
  Total body irradiation 1320 cGy+cyclophosphamide 120 mg/kg57 (47.9)
  Total body irradiation 1200 cGy+fludarabine 150 mg/m2+cytaratbine 9.0 mg/m27 (5.9)
  Fludarabine 150 mg/m2+busulfex 9.6 mg/kg14 (11.8)
  Busulfex (12.8 mg/kg)+cyclophosphamide 120 mg/kg6 (5.0)
Reduced intensity conditioning (N, %)35 (29.4)
  Total body irradiation 800 cGy+fludarabine 150 mg/m2+busulfex 6.4 mg/kg19 (16.0)
  Total body irradiation 800 cGy+fludarabine 150 mg/m2+cytaratbine 9.0 mg/m21 (0.8)
  Total body irradiation 400 cGy+fludarabine 150 mg/m2+busulfex 6.4 mg/kg12 (10.1)
  Fludarabine 150 mg/m2+busulfex 6.4 mg/kg3 (2.5)
Antithymocyte globulin
 None42 (35.3)
 1.25~2.5 mg/kg46 (38.7)
 5.0~10.0 mg/kg31 (26.1)
Median infused donor CD34+Cells at HSCT, ×106/kg (range)5.7 (0.1~21.1)
Median infused donor CD3+Cells at HSCT, ×106/kg (range)339.9 (2.9~901.4)
Graft-versus-host disease prophylaxis
 Methotrexate+cyclosporine45 (37.8)
 Methotrexate+tacrolimus66 (55.5)
 Mycophenolate mofetil+tacrolimus8 (6.7)
Post-transplant immune cell population, median frequency, %/MNC (range)
 CD3+T cells, N=11726.8 (0.218~88.3)
 CD4+T cells, N=1194.39 (0.002~54.0)
 CD8+T cells, N=11914.3 (0.107~56.7)
 CD56+cells, N=1174.757 (0.0~28.002)
 Natural killer cells (CD3CD56+), N=1178.1 (0.0~62.0)
 NKT-like cells (CD3+CD56+), N=1172.63 (0.004~20.6)
 Regulatory T cells (CD25+CD127low in CD3+CD4+cells), N=760.898 (0.0~22.996)
 invariant NKT cells (iNKT cells, Vβ11+CD3+), N=1170.061 (0.0~8.805)
 NKG2D expression on NK cells, N=1175.617 (0.025~40.906)
 NKG2D expression on NKT-like cells, N=1171.182 (0.0~11.921)
 MAIT cells (CD8+CD161+Vα7.2+), N=1190.429 (0.003~1.701)
 G-MDSC (HLA-DRLINCD11b+CD33+), N=1190.258 (0.009~13.4)
 M-MDSC (HLA-DRCD14+), N=1190.109 (0.004~4.325)

HCT-CI: hematopoietic cell transplantation-comorbidity index, HSCT: hematopoietic stem cell transplantation, MNC: mononuclear cell, NKT: natural killer T cell, NKG2D: natural killer group 2, member D, MAIT: mucosal associated invariant T cell, MDSC: myeloid-derived suppressor cell.

*HCT-CI was defined by Sorror et al. (21).


Multivariate analysis to identify factors affecting grade III–IV acute GVHD

VariablesGrade III–IV acute GVHD

HR (95% CI)p
Patient age (years, <40 vs="" 40="" td="">0.378 (0.129~1.109)0.076
Donor type (sibling, unrelated, haploidentical related, double cord)0.909 (0.41~2.012)0.81
Post-HSCT CD8+ T cells (%/MNCs, ≤5.8 vs. >5.8)0.453 (0.139~1.41)0.19
Post-HSCT iNKT cells (%/MNCs, ≤0.027 vs. >0.027)0.277 (0.091~0.844)0.024
Post-HSCT I-MDSCs (%/MNCs, ≤0.11 vs. >0.11)2.825 (0.848~9.417)0.091
Post-HSCT M-MDSCs (%/MNCs, ≤0.27 vs. >0.27)0.271 (0.078~0.937)0.039

GVHD: graft-versus-host disease, HSCT: hematopoietic stem cell transplantation, MNCs: mononuclear cells, iNKT cells: invariant natural killer cells, I-MDSCs: immature myeloid-derived suppressor cells, M-MDSCs: monocytic myeloid-derived suppressor cells.


Overall outcomes according to immune cells affecting GVHD-free, relapse-free survival

VariablesOverall survival at 1 year (95% CI)p-valueDisease-free survival at 1 year (95% CI)p-valueCumulative incidence of relapse at 1 years (95% CI)p-valueCumulative incidence of treatment-related mortality at 1 years (95% CI)p-value
iNKT cells0.4080.1690.080.975
 (NKT-like cell marking
 V β 11+CD3+)
 ≤0.02783.7% (64.5~93.0)79.6% (61.4~89.9)13.0% (4.7~25.8)7.3% (1.2~21.3)
 >0.02789.0% (78.0~94.7)85.7% (73.7~92.5)0.7% (2.1~16.1)7.3% (2.6~15.1)
M-MDSCs (HLA-DRCD14+)0.9840.350.0590.412
 ≤0.2785.7% (70.2~93.5)86.4% (71.4~93.9)3.5% (0.6~11.0)10.0% (3.0~22.2)
 >0.2788.2% (75.5~94.5)80.7% (66.8~89.3)13.8% (5.9~25.1)5.5% (1.4~13.8)

GVHD: graft-versus-host disease, iNKT cells: invariant natural killer cells, M-MDSCs: monocytic myeloid-derived suppressor cells.


Footnotes

Potential Conflict of Interest

The authors have no conflicting financial interest.

Supplementary Materials

Supplementary data including two tables and three figures can be found with this article online at http://pdf.medrang.co.kr/paper/pdf/IJSC/IJSC-11-s18094.pdf.

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