HLA-B*44 and the Bw4-80T motif are associated with poor outcome of relapse-preventive immunotherapy in acute myeloid leukemia

doi:10.21203/rs.3.rs-2860436/v1

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HLA-B*44 and the Bw4-80T motif are associated with poor outcome of relapse-preventive immunotherapy in acute myeloid leukemia

https://doi.org/10.21203/rs.3.rs-2860436/v1

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published 19 Aug, 2023

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HLA-B proteins interact with key immune receptors on both T and NK cells, and variants of the encoding gene are associated with outcomes in various pathologies, including autoimmune diseases and malignancies. HLA-B is pivotal in antigen presentation to cytotoxic T cells, and some variants containing a Bw4 motif also serve as ligands to the killer immunoglobulin-like receptors (KIR) 3DL1/S1 of NK cells. We investigated the potential impact of HLA-B genotypes on the efficiency of immunotherapy for relapse prevention in acute myeloid leukemia (AML). Seventy-nine non-transplanted AML patients receiving HDC/IL-2 in the post-consolidation phase were genotyped for HLA-B and KIRs genes. HLA-B*07 associated with improved leukemia-free survival (LFS), while HLA-B*44 heralded impaired LFS and overall survival (OS). The negative association with outcome was not shared across alleles of the HLA-B44 supertype. Notably, HLA-B*44 is one of few HLA-B44 supertype alleles containing a Bw4 motif with a threonine at position 80, which typically results in weak binding to the inhibitory NK receptor, KIR3DL1. Accordingly, a strong interaction between KIR3DL1 and Bw4 was associated with superior LFS and OS (p = 0.014 and p = 0.027, respectively). KIR3DL1⁺ NK cells from 80T-Bw4 donors showed significantly lower degranulation responses and cytokine responses than NK cells from 80I-Bw4 donors, suggesting impaired KIR3DL1-mediated education in 80T-Bw4 subjects. We propose that presence of a strong KIR3DL1⁺ - Bw4 interaction is advantageous in AML patients receiving immunotherapy for relapse prevention. This is likely achieved by improved NK cell education and a reduced expression of HLA-Bw4 on malignant leukemic cells.

NK cells

KIR3DL1

HLA-B*44

AML

IL-2

histamine

Acute myeloid leukemia (AML) is characterized by the infiltration of bone marrow and peripheral blood by immature myeloid cells [1]. Intensive induction chemotherapy yields high rates of complete remission (CR) but many patients relapse despite repeated courses of consolidation chemotherapy in the post-CR phase. Eligible patients may receive allogeneic stem cell transplants and older patients may benefit from post-consolidation chemotherapy for remission maintenance [2] but there remains a need for additional relapse-preventive therapies [3]. A phase III trial of 320 AML patients in remission showed that treatment with histamine dihydrochloride and interleukin-2 (HDC/IL-2) significantly improved leukemia-free survival (LFS) vs standard of care [4]. In this regimen, IL-2 activates natural killer (NK) and T cells, while HDC targets H₂ receptors expressed by myeloid cells to inhibit the formation of immunosuppressive oxygen radicals [5–7].

Human leukocyte antigen (HLA) class I genes are highly polymorphic genes that comprise nine supertypes (HLA-A1, -A2, -A3, -A24 and HLA-B7, -B27, -B44, -B58, -B62) [8]. The encoded proteins have a key role in antigen presentation, as peptides derived from intracellular proteins bind to the groove of the HLA molecule and are presented to cytotoxic CD8⁺ T cells. In this way, neoantigens from malignant cells are presented and can be detected by specific T cells ideally leading to the elimination of malignant cells. Like T cells, NK cells express a battery of receptors that recognize HLA molecules, such as the killer immunoglobulin-like receptors (KIRs). The KIR locus harbors a family of highly homologous and polymorphic genes, and the encoded receptors recognize specific HLA molecules. Thereby, NK cells will in general spare healthy cells with intact expression of HLA class I molecules, while cells with absent or reduced HLA class I expression will fail to generate sufficient inhibitory signals in NK cells and are killed in a process known as missing self-recognition.

All HLA-C alleles serve as ligands to KIR2D receptors, while subsets of HLA-A and HLA-B alleles contain a Bw4 motif that ligates KIR3DL1. A dimorphism at position 80, with isoleucine (Bw4-80I) or threonine (Bw4-80T) variants, has been reported to determine the affinity for KIR3DL1 [9]. Interestingly, such Bw4 variants were reported to be of clinical relevance in viral infections and malignancies [10–12]. Additionally, HLA gene variants may impact on the efficiency of cancer immunotherapy. For example, HLA-A*03 has been proposed to negatively predict outcome of immune checkpoint blockade (ICB) therapy [13]. In ICB-treated melanoma, the HLA-B44 supertype was associated with prolonged survival, while individuals carrying the HLA-B62 supertype showed poor outcome [14]. However, the beneficial impact of the B44 supertype was not observed in lung cancer [15], B-cell lymphoma (DLBCL) [16] or uveal melanoma [17].

This study aimed at determining the potential impact of HLA-B genotypes on outcome of HDC/IL-2-based immunotherapy in AML. We observed that HLA-B*44, but not other members of the HLA-B44 supertype, was associated with distinctly poor LFS. Notably, the HLA-B*44 alleles encode an Bw4-80T motif with low affinity for KIR3DL1. Individuals with this Bw4 variant harbored KIR3DL1⁺ NK cells with inferior degranulation and cytokine release responses to leukemic cells, which may contribute to the poor survival after AML immunotherapy.

Patients

An open-label single-arm phase IV study (Re:Mission, NCT01347996) enrolled 84 (age 18–79) patients in first CR with de novo or secondary AML. Patients received ten 21-day cycles of HDC (0.5 mg by subcutaneous injection twice daily) and IL-2 (16 400 IU/kg by subcutaneous injection twice daily) for 18 months or until relapse/death. A primary objective of the study was to monitor quantitative and qualitative pharmacodynamics effects with focus on the phenotype and function of NK cells, T cells and myeloid cells. All patients gave written informed consent prior to enrollment and the trial was approved by the Ethical committees in all participating regions. This study was conducted according to the Declaration of Helsinki principles. Results from the trial have been previously published [18–21]. Detailed patient characteristics can be found in previously published papers [18, 19].

Sampling of peripheral blood

Peripheral blood was collected before and after the first and third treatment cycles. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation using Lymphoprep (Stemcell Technologies) and cryopreserved at local sites and shipped on dry ice to the central laboratory at University of Gothenburg for analysis by flow cytometry. Samples with < 25% viability were excluded from any analyzes.

Leukopacks from healthy blood donors were obtained from Sahlgrenska University Hospital, and PBMCs were isolated by density gradient centrifugation using Lymphoprep (Stemcell Technologies) and cryopreserved in liquid nitrogen. Isolation of NK cells was performed by negative selection using human NK cell isolation kit (Miltenyi Biotec) in accordance with manufacturer’s instructions.

DNA extraction and KIR/HLA genotyping

DNA was extracted from whole blood using a Roche MagNAPure 96 or Qiagen^® DNeasy Blood & Tissue kit according to the manufacturer’s instructions. KIR typing was performed using the One Lambda KIR SSO Genotyping Test. When the analysis generated conflicting results for certain KIR alleles, the Olerup SSP KIR genotyping kit was used to determine the KIR genotype. KIR ligands were determined using the Olerup SSP KIR HLA Ligand kit. Patients were dichotomized based on the concordance/discordance between their KIR and HLA genotypes.

Functional assays

NK cells were cultured overnight with 100 IU/ml of IL-2 (Proleukin, Novartis Pharmaceuticals) or non-stimulated (resting) in 0.1 million cells/well before addition of 0.1 million K562 cells/well. Anti-CD107a-BUV395 (H4A3, BD Biosciences) was added to measure the degranulation. After 4 hours incubation, cells were stained with anti-CD56-BV711 (NCAM 16.2, BD Biosciences), anti-NKG2A-PE (Z199), anti-KIR2DL1/S1-PE-Cy7 (EB6B), anti-KIR2DL2/L3/S2-PE-Cy5.5 (GL183; all Beckman Coulter) and anti-KIR3DL1-APC (DX9, Biolegend).

In intracellular cytokine assays, 50 000 NK cells/well were cultured and stimulated overnight, using same conditions as in degranulation assays. A five-hour co-culture with 50 000 K562 cells/well at 37°C was performed, adding Brefeldin A (GolgiPlug, BD Biosciences) after one hour. The cells were stained with the same antibodies as mentioned above, followed by fixation and permeabilization with BD Cytofix/Cytoperm (BD Biosciences). At the end, cells were stained with anti-IFNg-BUV395 (B27) and anti-TNFα-AF488 (Mab 11; both BD Biosciences).

Stained samples were analyzed using on a five laser BD LSR Fortessa SORP instrument. Data was analyzed using FACSDiva (v.8.0.1 or later) and FlowJo (v.10.8.1) software (BD Biosciences).

Statistical analyses

All statistical analyses were performed in Prism version 9 or later (GraphPad Software). The logrank test (Mantel-Cox) was used to compare survival between patient groups. Incidence of relapse was calculated using Fisher’s exact and Chi square tests. The impact of HLA B alleles on LFS was analyzed by univariate Cox regression analysis in SPSS. Mann-Whitney test was used to compare responses in degranulation and intracellular cytokine staining assays between groups.

HLA-B*44 associates with inferior leukemia-free survival

Seventy-six patients from the Re:Mission trial were genotyped for HLA-B alleles. Out of 24 detected alleles, the most common was B*44 (detected in 28% of patients, allele frequency = 0.15), followed by B*35 (21%, 0.11), B*7 (20%, 0.11) and B*8 (20%, 0.11). The other alleles detected in > 10% of patients were B*51 and B*40 (Table 1).

To determine whether HLA B allotypes had an impact on clinical outcome, we performed univariate Cox regression analyses of leukemia-free survival (LFS) for all alleles with an allele frequency of > 10% in the cohort. As shown in Table 1, HLA-B*07 was associated with improved LFS, while patients with at least one HLA-B*44 allele showed significantly inferior LFS. Accordingly, Kaplan-Meier survival analyses showed that patients harboring an HLA-B*44 (n = 21) allele had inferior LFS and overall survival (OS) when compared to patients with other alleles (n = 55) (Fig. 1a-b; p = 0.0007 and p = 0.008, respectively).

Table 1

HLA-B allele frequency and impact on LFS
Allele	Detected in % patients	Allele frequency	Univariate Cox regression analysis of LFS
B*07	20%	0.112	0.048
B*08	20%	0.105	0.345
B*35	21%	0.112	0.944
B*40	14%	0.072	0.596
B*44	28%	0.151	< 0.001
B*51	17%	0.086	0.486

Some HLA-B alleles display a similar capacity to bind and present peptides, and such alleles are thus commonly grouped into supertypes [22]. Survival analyses comparing the B44 supertype (n = 41) with all other B supertypes (n = 35) showed significantly superior LFS for patients who did not carry any B44 supertype alleles (p < 0.05; Fig. 2a). However, the effect of the B44 supertype on clinical outcome was clearly driven by HLA-B*44 alleles as the incidence of relapse was significantly higher in B*44 allele carriers (n = 21) than in non-B*44 allele carriers (n = 20) within the HLA-B44 supertype (Fig. 2b-c).

Patients with Bw4-80T have inferior clinical outcome

As stated above, HLA supertypes are groups of HLA alleles that share peptide binding features that allow them to present similar antigens to T cells. Although recent studies have demonstrated that some NK cell receptors display peptide specificity [23], HLA interactions with NK cell receptors are typically less dependent on the presented peptide. NK cells are reportedly important for clinical outcome of HDC/IL-2 immunotherapy in AML [18, 19, 24–26]. We hypothesized that the discrepancy regarding impact on outcome of patients within the HLA-B44 supertype might be related to differential capacity of the encoded HLA-B molecules to interact with NK cell receptors. HLA-B molecules contain either a Bw6 motif that does not interact with NK cell receptors, or one of two different Bw4 motifs, Bw4-80I and Bw4-80T, which are recognized by the NK cell receptor KIR3DL1 [27]. Interestingly, data from the Immune polymorphism database showed that there are large differences within the B44 supertype regarding presence of Bw4 or Bw6 motifs [28].

HLA-B*44 and HLA-B*37 alleles harbor the Bw4-80T motif, the HLA-B*49 allele contains a Bw4-80I motif, while the remaining major HLA-B44 supertype alleles encode the Bw6 motif. Thus, we next tested if relapse incidence was associated with Bw4 and Bw6 motifs. As shown in Fig. 3-b, patients with at least one Bw4-80T allele had significantly higher relapse rates and inferior survival.

Strong interacting 3DL1/Bw4 pair favors leukemia-free survival

Different combinations of KIR3DL1 and Bw4-containing HLA-B alleles result in 3DL1-Bw4 interactions of varying affinity. KIR3DL1 alleles are divided into subgroups based on surface expression and function, and the subtypes KIR3DL1-high or KIR3DL1-low bind Bw4-80I and 80T with different affinity. We thus genotyped all Bw4⁺ patients for KIR3DL1 alleles and grouped them into those predicted with a strong KIR3DL1-Bw4 interaction (at least one KIR3DL1-high allele along with a Bw4-80I allele) or a weak interaction (KIR3DL1-low together with either of the two Bw4 motifs). As shown in Fig. 4a-b, patients with a strong interacting pair (n = 19) showed significantly improved LFS and OS compared to patients with a weak interacting pair (n = 24).

To address the possible mechanisms underlying the inferior outcome for Bw4-80T patients, we first determined the education status and ability to mount a missing-self response in KIR3DL1-single positive (sp) NK cells. In agreement with previous reports [29] there were significant differences between KIR3DL1⁺ NK cells from 80T to 80I individuals in degranulation assays towards HLA-negative, NK cell-sensitive K562 cells. In the presence or absence of IL-2 pre-stimulation, the KIR3DL1⁺ NK cells from Bw4-80I donors degranulated significantly more than KIR3DL1⁺ NK cells from Bw4-80T donors (Fig. 5a). A similar pattern of increased NK cell responses to K562 cells within the Bw4-80I group was observed for IFNγ and TNFα production (Fig. 5b-c).

HLA-B is a highly polymorphic molecule in immune cell recognition of malignant cells, and HLA-B genotypes have been linked to disease severity and treatment outcome in various pathologies. In this study, we set out to determine to what extent HLA-B genotypes are associated with treatment outcome in AML patients receiving immunotherapy for relapse prevention. Our results imply that AML patients with at least one B*07 allele show superior outcome in terms of LFS. We hypothesize that this finding is explained by the parallel encoding of an HLA-E-presentable leader peptide with a methionine residue in position 2 (HLA-B -21M), which is associated with improved effector functions of NKG2A⁺ NK cells [26]. However, the most striking finding in our study was that patients carrying B*44 alleles showed significantly inferior LFS and OS after HDC/IL-2 treatment. In contrast to these findings, ICB-treated melanoma patients with HLA-B44 supertype alleles reportedly show prolonged survival [14]. It was proposed that the B44 supertype encompasses an electropositive binding pocket to preferentially display peptides with negatively charged amino acid anchors, which are common among melanoma neoantigens [14].

In our study the association with outcome appeared to be specific for the B*44 alleles as patients carrying HLA-B*44 alleles showed inferior outcome vs patients carrying non-HLA-B*44 alleles within the B44 supertype. Supertypes comprise HLA alleles that share peptide preferences, but within one HLA B supertype, the ability to serve as a KIR3DL1 ligand may vary. Within the B44 supertype, HLA B*37 and B*44 contain the Bw4-80T epitope, which is a weak ligand to KIR3DL1 while other alleles encode either Bw6 or Bw4-80I, with the latter typically showing high affinity to KIR3DL1 [9, 28, 30, 31]. Intuitively, a weak inhibitory interaction between NK cells and leukemic targets should be advantageous and favor NK cell cytotoxicity. However, a weak interaction also means that the homeostatic inhibitory signaling to circulating NK cells via KIR3DL1 is low. These signals set the functional threshold for NK cells in a process known as education [32]. The more inhibitory input the NK cell receives at steady-state, the more vigorously the cell can respond to a target with down-regulated MHC class I expression. Accordingly, our data indicated that individuals carrying HLA-B Bw4-80T harbored less functional single-positive KIR3DL1⁺ NK cells than donors with Bw4-80I, which is in agreement with previous reports [29]. Notably, it was reported that AML blasts display lower expression of HLA-Bw4 antigens than cells from healthy volunteers [33]. It is thus conceivable that NK cells can exert missing-self cytotoxicity against AML blasts, and that the response may be stronger if these anti-leukemic cells are highly educated via KIR3DL1 interactions with the high-affinity Bw4-80I ligands.

In line with this reasoning, studies of HIV infection show that NK cells from individuals with strong educating KIR3DL1 - Bw4 interactions mount more efficient cytotoxic responses to HIV-infected cells [34] and that such individuals are less likely to progress to AIDS [12]. Furthermore, in uveal melanoma, which is a rare malignancy in which NK cells are believed to be key mediators in preventing metastasis formation, HLA-B*44 allele carriers were reported to have a significantly inferior survival [17]. The interaction between KIR3DL1 and Bw4 variants has also been the focus of multiple studies of allogeneic stem cell transplantation in AML. Some studies have, in contrast to the studies above, suggested reduced relapse risk and a survival benefit in patients receiving grafts resulting in low KIR3DL1 inhibition [35, 36] but a large retrospective study of over 2,000 transplanted patients did not confirm these results [37]. More studies are thus warranted to clarify the role of KIR3DL1 - Bw4 interactions in transplanted and non-transplanted AML.

In summary, we show that expression of host HLA-B*44 is associated with inferior survival in AML patients receiving immunotherapy for relapse prevention. We hypothesize that this HLA-B variant, which is a weak ligand to the NK cell receptor, KIR3DL1, results in hypofunctional KIR3DL1⁺ NK cells that fail to mount strong anti-leukemic responses.

Author contributions

Hana Komic, Alexander Hallner, Elin Bernson, Kristoffer Hellstrand and Fredrik Bergh Thorén designed the research; Hana Komic, Alexander Hallner, Elin Bernson, Chiara Badami, Anne Wöhr, and Brwa Ali Hussein performed research and analyzed data; Kristoffer Hellstrand, Elin Bernson, and Fredrik Bergh Thorén supervised the study; Hana Komic and Fredrik Bergh Thorén wrote the manuscript, and all authors reviewed the manuscript.

Acknowledgments

This work was supported by the Swedish Research Council, the Swedish Cancer Society, the Swedish state via the ALF agreement, the Assar Gabrielsson Foundation, the Wilhelm and Martina Lundgren Research Foundation, BioCARE, and the Sahlgrenska Academy at the University of Gothenburg.

Competing Interests

K.H. and F.B.T. are authors of issued or pending patents protecting the use of HDC in cancer immunotherapy. The remaining authors declare no competing financial interests.

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Competing interest reported. K.H. and F.B.T. are authors of issued or pending patents protecting the use of HDC in cancer immunotherapy. The remaining authors declare no competing financial interests.

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HLA-B*44 and the Bw4-80T motif are associated with poor outcome of relapse-preventive immunotherapy in acute myeloid leukemia

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Abstract

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Introduction

Materials and methods

Patients

Sampling of peripheral blood

DNA extraction and KIR/HLA genotyping

Functional assays

Results

HLA-B*44 associates with inferior leukemia-free survival

Patients with Bw4-80T have inferior clinical outcome

Strong interacting 3DL1/Bw4 pair favors leukemia-free survival

Discussion

Declarations

References

Additional Declarations

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Journal Publication

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