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• W2477932914 abstract "•Higher CD8+ T-cell dose (CD8hi) in peripheral blood stem-cell grafts was associated with improved survival due to a reduction in the risk for cancer relapse without a significant increase in graft-versus-host disease.•While only young donors produced CD8hi grafts, donor age alone was not a sufficient predictor of outcomes in reduced intensity allogeneic stem-cell transplantation.•The CD4:CD8 ratio in the peripheral blood predicts CD8hi donors and could serve as an important donor screening tool.•Screening donors for their potential to mobilize grafts with high CD8+ T cell content could lead to significant improvements in reduced intensity transplant outcomes. HLA-identical siblings have always been considered ideal donors for allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in the treatment of hematologic cancers. Recent data suggest that we should rethink this paradigm. In “High Graft CD8+ Cell Dose Predicts Improved Survival and Enables Better Donor Selection in Allogeneic Stem-Cell Transplantation With Reduced-Intensity Conditioning,” we identified a group of stem-cell donors whose grafts contain an optimal composition of T-cells, leading to a dramatic decrease in disease relapse risk and an improvement in overall survival following allo-HSCT. To demonstrate this, we analyzed the outcomes of 200 patients with hematologic malignancies who underwent allo-HSCT after reduced-intensity conditioning (RIC). The analysis focused on T-cell content of peripheral blood stem-cell grafts. We found that higher graft CD8+ T-cell dose (CD8hi), a trait found only in grafts collected from young donors, was associated with improved survival due to a reduction in the risk for cancer relapse without a significant increase in graft-versus-host disease (GVHD). Though not all young donors mobilized CD8hi grafts, we found that a low CD4:CD8 ratio in the peripheral blood could identify these ideal donors prior to transplant. The likelihood of finding CD8hi donors correlated inversely with age, and elderly RIC transplant recipients had a low chance of receiving an ideal graft from their similarly aged siblings. Here, we examine these findings and their implications on choosing donors according to age and relatedness. We also explore biological mechanisms that determine the CD4:CD8 ratio in healthy donors. HLA-identical siblings have always been considered ideal donors for allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in the treatment of hematologic cancers. Recent data suggest that we should rethink this paradigm. In “High Graft CD8+ Cell Dose Predicts Improved Survival and Enables Better Donor Selection in Allogeneic Stem-Cell Transplantation With Reduced-Intensity Conditioning,” we identified a group of stem-cell donors whose grafts contain an optimal composition of T-cells, leading to a dramatic decrease in disease relapse risk and an improvement in overall survival following allo-HSCT. To demonstrate this, we analyzed the outcomes of 200 patients with hematologic malignancies who underwent allo-HSCT after reduced-intensity conditioning (RIC). The analysis focused on T-cell content of peripheral blood stem-cell grafts. We found that higher graft CD8+ T-cell dose (CD8hi), a trait found only in grafts collected from young donors, was associated with improved survival due to a reduction in the risk for cancer relapse without a significant increase in graft-versus-host disease (GVHD). Though not all young donors mobilized CD8hi grafts, we found that a low CD4:CD8 ratio in the peripheral blood could identify these ideal donors prior to transplant. The likelihood of finding CD8hi donors correlated inversely with age, and elderly RIC transplant recipients had a low chance of receiving an ideal graft from their similarly aged siblings. Here, we examine these findings and their implications on choosing donors according to age and relatedness. We also explore biological mechanisms that determine the CD4:CD8 ratio in healthy donors. HLA-identical siblings have always been considered ideal donors for allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in the treatment of hematologic cancers; however, recent data suggest that we should rethink this paradigm. In a previous article [1Reshef R. Huffman A.P. Gao A. et al.High graft CD8 cell dose predicts improved survival and enables better donor selection in allogeneic stem-cell transplantation with reduced-intensity conditioning.J Clin Oncol. 2015; 33: 2392-2398Crossref PubMed Scopus (39) Google Scholar], we identified a group of stem cell donors whose grafts contained an optimal composition of T cells, leading to a dramatic decrease in disease relapse risk and improved overall survival after allo-HSCT. To demonstrate this, we analyzed the outcomes of 200 patients with hematologic malignancies who underwent allo-HSCT after reduced-intensity conditioning (RIC). The analysis focused on T-cell content of peripheral blood stem-cell grafts. We found that higher graft CD8+ T-cell dose (CD8hi), a trait found only in grafts collected from young donors, was associated with improved survival due to a reduction in the risk for cancer relapse without a significant increase in graft-versus-host disease (GVHD). Although not all young donors mobilized CD8hi grafts, we found that a low CD4:CD8 ratio in the peripheral blood could identify these ideal donors before transplantation. The likelihood of finding CD8hi donors correlated inversely with age and elderly RIC transplantation recipients had a low chance of receiving an ideal graft from their similarly aged siblings. Here, we examine these findings and their implications for choosing donors according to age and relatedness. We also explore biological mechanisms that determine the CD4:CD8 ratio in healthy donors. In our previous study, we found that the graft T-cell dose had a drastic impact on the outcomes of RIC transplantations [1Reshef R. Huffman A.P. Gao A. et al.High graft CD8 cell dose predicts improved survival and enables better donor selection in allogeneic stem-cell transplantation with reduced-intensity conditioning.J Clin Oncol. 2015; 33: 2392-2398Crossref PubMed Scopus (39) Google Scholar]. The importance of an adequate CD8+ T-cell dose in allo-HSCT has been demonstrated previously in smaller cohorts [2Cao T.M. Shizuru J.A. Wong R.M. et al.Engraftment and survival following reduced-intensity allogeneic peripheral blood hematopoietic cell transplantation is affected by CD8+ T-cell dose.Blood. 2005; 105: 2300-2306Crossref PubMed Scopus (51) Google Scholar, 3Moscardó F. Sanz J. Carbonell F. et al.Effect of CD8+ cell content on umbilical cord blood transplantation in adults with hematological malignancies.Biol Blood Marrow Transplant. 2014; 20: 1744-1750Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. In our study, grafts had significant heterogeneity in T-cell content, with greater than a log difference in T-cell numbers between smaller and larger grafts. CD8+ T-cell dose was correlated inversely with donor age, whereas CD4+ dose was not. Although only 13% of donors older than age 50 produced CD8hi grafts, approximately 40% of donors younger than age 50 produced such grafts. Importantly, CD8+ T-cell dose was an independent predictor of disease relapse and a high CD8+ T-cell dose was associated with more rapid T-cell engraftment, but not with higher rates of GVHD or nonrelapse mortality. Patients who received CD8hi grafts also saw improved overall and relapse-free survival despite the inclusion of many single-allele-mismatched donors in this group. Donor age alone was not a sufficient predictor of the CD8+ T-cell dose and the outcomes of patients receiving transplantations from young versus old donors were not different if the CD8+ T-cell dose was not taken into account. RIC allo-HSCT recipients had improved overall survival when they received CD8hi grafts from younger donors, but not if they received CD8lo grafts from other donors, young or old. Our findings appear to identify donor age as a key contributor to RIC allo-HSCT outcomes. The impact of donor age on transplantation outcomes has been explored extensively. Kollman et al. studied almost 7,000 unrelated bone marrow transplantations and found that donor age was inversely correlated with overall and disease-free survival [4Kollman C. Howe C.W. Anasetti C. et al.Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age.Blood. 2001; 98: 2043-2051Crossref PubMed Scopus (521) Google Scholar]. Different rates of acute and chronic GVHD, but not of disease relapse, drove this association. In contrast, Rezvani et al. found no significant difference in nonrelapse mortality between donors more than 60 years of age and younger donors, although only 8% of donors were older than age 60 in their study [5Rezvani A.R. Storer B.E. Guthrie K.A. et al.Impact of donor age on outcome after allogeneic hematopoietic cell transplantation.Biol Blood Marrow Transplant. 2015; 21: 105-112Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar]. They also found that grafts from older siblings produced less acute GVHD than grafts from young, unrelated donors, but relapse rates and survival were not reported. Alousi et al. conducted the largest contemporary study comparing older siblings with younger unrelated donors [6Alousi A.M. Le-Rademacher J. Saliba R.M. et al.Who is the better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer?.Blood. 2013; 121: 2567-2573Crossref PubMed Scopus (82) Google Scholar]. They analyzed a heterogeneous cohort of 2172 transplantation procedures registered in the Center for International Blood and Marrow Transplant Research in patients over the age of 50. In a subset of patients with good performance scores, grafts from older sibling donors led to a survival advantage driven by lower rates of relapse and nonrelapse mortality [6Alousi A.M. Le-Rademacher J. Saliba R.M. et al.Who is the better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer?.Blood. 2013; 121: 2567-2573Crossref PubMed Scopus (82) Google Scholar]. Outcomes were similar for both donor types in patients with lower performance scores. What appear to be discordant results between these studies most likely stems from differences in disease mix, graft source, and conditioning regimens that were used in the studied cohorts, making their conclusions difficult to apply to clinical practice. In our study, only young donors produced CD8hi grafts, but donor age alone was not associated with improved outcomes. Myelodysplastic syndrome (MDS) is the only disease in which we were able to demonstrate an independent effect of donor age and relatedness regardless of CD8+ T-cell dose [7Yam C. Crisalli L. Luger S.M. et al.Unrelated donors are associated with improved relapse free survival compared to related donors in patients with myelodysplastic syndrome undergoing reduced intensity allogeneic stem-cell transplantation.Am J Hematol. 2016; 91: 883-887Crossref PubMed Scopus (3) Google Scholar]. The reason is that MDS affects older individuals, so, because of a vast age gap between sibling donors and unrelated donors, an advantage for young unrelated donors appeared to be independent of other factors. Age-related variables that may affect allo-HSCT outcomes include differences in the phenotype and function of HSCs and T cells. Human HSCs increase in frequency with age, become less quiescent, and exhibit more myeloid-biased differentiation potential [8Pang W.W. Price E.A. Sahoo D. et al.Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age.Proc Natl Acad Sci U S A. 2011; 108: 20012-20017Crossref PubMed Scopus (500) Google Scholar]. Aged HSCs upregulate transcriptionally genes associated with the cell cycle and myeloid lineage specification. This bias towards myeloid differentiation may lead to slower recovery of the lymphoid compartment, slower immunologic reconstitution, and functionally different mature T cells that arise from aged HSCs. Although not well characterized, these differences may have an impact on the GVH and graft-versus-leukemia (GVL) responses that determine allo-HSCT outcomes. CD8+ T cells undergo age-related changes in phenotype, function, and compartmentalization that affect the type and number of T cells in stem-cell grafts that are harvested from peripheral blood. Memory T cells are a minority of circulating CD8+ T cells at any age, but the proportion between effector and naive T cells varies significantly with age [9Sathaliyawala T. Kubota M. Yudanin N. et al.Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets.Immunity. 2013; 38: 187-197Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar]. Thome et al. examined the spatial regulation of human T cells throughout life [10Thome J.J. Yudanin N. Ohmura Y. et al.Spatial map of human T cell compartmentalization and maintenance over decades of life.Cell. 2014; 159: 814-828Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar] and found that naive CD8+ T cells localize to blood and lymphoid tissue and the proportion of naive CD8+ T cells decreases with age, whereas effector and memory CD8+ T cells increase. These changes are likely the result of increased antigen exposure over time. It is therefore possible that CD8hi grafts from younger donors contain a higher number of naive CD8+ T cells that are responsible for a potent GVL effect. Although they did not examine donor age directly, Beatty et al. found that, after allo-HSCT, leukemia-antigen-specific CD8+ T cells can become functionally unresponsive due to replicative senescence and telomere shortening [11Beatty G.L. Smith J.S. Reshef R. et al.Functional unresponsiveness and replicative senescence of myeloid leukemia antigen-specific CD8+ T cells after allogeneic stem cell transplantation.Clin Cancer Res. 2009; 15: 4944-4953Crossref PubMed Scopus (33) Google Scholar]. Older donors therefore create a theoretical disadvantage because of a similar age-related senescence that limits their expansion and may impair their ability to mount a GVL response. Donor telomere length has also been examined in allo-HSCT for aplastic anemia, a nonmalignant disorder, and was found to be associated with outcome [12Gadalla S.M. Wang T. Haagenson M. et al.Association between donor leukocyte telomere length and survival after unrelated allogeneic hematopoietic cell transplantation for severe aplastic anemia.JAMA. 2015; 313: 594-602Crossref PubMed Scopus (56) Google Scholar]. Our findings suggest that the donor CD4:CD8 ratio indicates the potency of the GVL response. Therefore, it is critical to understand what factors are responsible for the variability in this ratio among normal donors. These factors may play an important role in allo-HSCT and also in adoptive cell therapies such as those using chimeric antigen receptor T cells and other forms of cancer immunotherapy. Prior studies have shown a hereditary component to the CD4:CD8 ratio, possibly determined by a major recessive gene with a polygenetic component [13Amadori A. Zamarchi R. De Silvestro G. et al.Genetic control of the CD4/CD8 T-cell ratio in humans.Nat Med. 1995; 1: 1279-1283Crossref PubMed Scopus (334) Google Scholar]. However, genome-wide association studies did not identify such a gene, but rather suggested that the CD4+ and CD8+ populations are regulated through independent quantitative trait loci [14Ferreira M.A. Mangino M. Brumme C.J. et al.Quantitative trait loci for CD4:CD8 lymphocyte ratio are associated with risk of type 1 diabetes and HIV-1 immune control.Am J Hum Genet. 2010; 86: 88-92Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. These loci explain only 8% of the variability in the CD4:CD8 ratio, limiting our ability to conclude much from this evidence. Environmental contributors to the CD4:CD8 ratio are also not easy to determine, but viral infection is an obvious culprit because CD8+ T cells proliferate rapidly during viral infection. Tripp et al. noted that, in mice, CD8+ T cells are normally present in the spleen and lymph nodes in lower numbers than CD4+ T cells, but during viral infections, they expand to outnumber CD4+ T cells [15Geiselhart L.A. Humphries C.A. Gregorio T.A. Mou S. Subleski J. Komschlies K.L. IL-7 administration alters the CD4:CD8 ratio, increases T cell numbers, and increases T cell function in the absence of activation.J Immunol. 2001; 166: 3019-3027Crossref PubMed Scopus (114) Google Scholar]. This expansion, although likely multifactorial, can be at least partially traced to circulating interleukins, primarily IL-7 [16Tripp R.A. Hamilton-Easton A.M. Cardin R.D. et al.Pathogenesis of an infectious mononucleosis-like disease induced by a murine gamma-herpesvirus: role for a viral superantigen?.J Exp Med. 1997; 185: 1641-1650Crossref PubMed Scopus (141) Google Scholar, 17Sun J.C. Lehar S.M. Bevan M.J. Augmented IL-7 signaling during viral infection drives greater expansion of effector T cells but does not enhance memory.J Immunol. 2006; 177: 4458-4463Crossref PubMed Scopus (49) Google Scholar]. Cytokine effects can cause CD8+ T cells to proliferate up to 12-fold and can change the CD4:CD8 ratio within days. The length of time that the CD4:CD8 ratio would remain altered after a viral infection is largely unknown and the kinetics of this immune activation are likely virus specific. In our study, cytomegalovirus (CMV) serostatus was not associated with the CD4:CD8 ratio. However, CMV serostatus does reflect past exposure to the virus and is not reflective of active viral proliferation, which could be more critical to CD8+ proliferation. To complicate things further, the magnitude of CD8+ proliferation in response to viral infection may also depend on polymorphisms in IL receptors and other host factors. How should we apply these findings clinically? First, the protective effect of CD8hi grafts against relapse appears to be specific to transplantations performed with RIC, in which disease relapse rates of 30–50% have been described [18Reshef R. Porter D.L. Reduced-intensity conditioned allogeneic SCT in adults with AML.Bone Marrow Transplant. 2015; 50: 759-769Crossref PubMed Scopus (28) Google Scholar]. In myeloablative transplantations, Cao et al. found that the dose of T cells or their major subsets did not affect outcomes [19Cao T.M. Wong R.M. Sheehan K. et al.CD34, CD4, and CD8 cell doses do not influence engraftment, graft-versus-host disease, or survival following myeloablative human leukocyte antigen-identical peripheral blood allografting for hematologic malignancies.Exp Hematol. 2005; 33: 279-285Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. Waller et al. reported similar negative findings for the Blood and Marrow Transplant Clinical Trials Network [20Waller E.K. Logan B.R. Harris W.A. et al.Improved survival after transplantation of more donor plasmacytoid dendritic or naive T cells from unrelated-donor marrow grafts: results from BMTCTN 0201.J Clin Oncol. 2014; 32: 2365-2372Crossref PubMed Scopus (66) Google Scholar]. This lack of association between T-cell doses and outcome may be because the GVL response plays only a partial role in myeloablative transplantations, whereas RIC transplantations rely solely on the GVL response to cure malignancy. In addition, studies of myeloablative transplantations generally enroll patients up to an upper age limit of 50 or 60 years, so their donors tend to be young. Additional factors such as sample size and disease mix may have concealed the effect of T-cell graft content on myeloablative transplantation outcomes. Second, an easy and feasible way to identify ideal donors should be determined. The changes in hematopoiesis and T-cell phenotype that result in drastic differences in graft content are age related, but donor age alone is not a sufficient predictor of outcome. A more direct way to improve donor selection would be to screen donors for their potential to mobilize grafts with high CD8+ T-cell content, which could lead to significant improvements in RIC transplantation outcomes. Previously, we examined 21 allo-HSCT donors to evaluate traits in the peripheral blood that could predict high CD8+ graft dose. Donors with a higher proportion of CD8+ cells or a low CD4:CD8 ratio in the peripheral blood mobilized grafts with higher CD8+ cell doses [1Reshef R. Huffman A.P. Gao A. et al.High graft CD8 cell dose predicts improved survival and enables better donor selection in allogeneic stem-cell transplantation with reduced-intensity conditioning.J Clin Oncol. 2015; 33: 2392-2398Crossref PubMed Scopus (39) Google Scholar]. Taken together, our findings suggest that ideal allo-HSCT donors can be identified through T-cell characteristics, mainly their CD4:CD8 ratio. There are myriad contributors, from genetic predisposition to environmental factors, to a donor's CD4:CD8 T-cell ratio and it remains to be determined how this ratio affects the antitumor response in the recipient. Methods to identify these ideal donors must be investigated prospectively. This work was supported by the Conquer Cancer Foundation , the National Marrow Donor Program , the Department of Defense (Grant No. CA120381 ), and the National Cancer Institute (Grant No. K23CA178202 )." @default.
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• W2477932914 title "Precision in donor selection: Identifying ideal stem-cell donors through their T cells" @default.
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