Killer-cell immunoglobulin-like receptor genomics and haematopoietic progenitor cell transplantation: Utilising allelic polymorphism within donor selection algorithms

Abstract

The highly polymorphic killer-cell immunoglobulin receptor (KIR) genes encode some of the key receptors involved in regulation of the cytotoxic action of natural killer (NK) cells, facilitating clearance of virally infected and neoplastic cells. To investigate how the KIR complex effects the outcome of selected haematopoietic progenitor cell transplantation (HPCT) programmes, next generation sequencing was used to evaluate allelic polymorphism of KIR, in a single transplant centre cohort (n=281), to construct a refined model for transplant donor selection. The viability of more cost- effective donor KIR assessments was also explored. High levels of KIR diversity in both gene content and allelic polymorphism was evident, and no KIR donor selection model studied influenced 3-year overall survival event-free survival or reduce relapse incidence in the cohort (n=115). The impact of allelic polymorphism of KIR2DL1, 2DL2, and 2DL3 upon post-transplant outcomes was investigated in two patient groups: Cohort A (KIR2DL1 n=113, KIR2DL2/3 n=114) encompassing all transplants in the sample, and Cohort B (KIR2DL1 n=86, KIR2DL2/3 n=87), a sub-cohort of T cell depleted reduced intensity conditioning transplants. Close linkage between the allele groups of KIR2DL1, 2DL2, and 2DL3 negated the value of independent analysis into KIR2DL1 and 2DL3, and the KIR2DL2*001 group was identified as acting as a weak proxy for KIR B/x diplotype profiles (present in 76.6% of KIR B/x donors). Examination of three distinct donor KIR2DL1 allele groups (KIR2DL1*001/002, 003, and 004) identified KIR2DL1*003 positive donors as detrimental to post-transplant outcomes, reducing 3-year overall survival (OS) (36.5% vs 61.8%, p=0.046, pc=0.184) and event-free survival (EFS) (28.9% vs 58.8%, p=0.015, pc=0.084), and increasing 3-year relapse incidence (54.1% vs 21.9%, p=0.019, pc=0.090). This data suggests KIR2DL1*003 positive donors should be avoided in the setting of T cell depleted reduced intensity conditioning HPCT. The described cohort data was further interrogated to investigate the clinical value of KIR2DL1 signature single motif (codon 114 and 245) assessments, with the aim of reducing the financial cost of testing for these donor characteristics. This showed that donor KIR2DL1 with proline at position 114 (KIR2DL1-P114) provided improved OS (58.8% versus 28.6%, p=0.008, pc=0.032), EFS (51.0% versus 25.7%, p=0.018, pc=0.060), and reduced incidence of relapse (31.5% versus 54.9%, p=0.028, pc=0.084) compared to transplants using KIR2DL1-P114 negative donors. In contrast, transplants where donors possessed leucine at position 114 (KIR2DL1-L114) exhibited decreased 3-year OS (36.5% versus 61.8%, p=0.046, pc=0.138) and EFS (28.9% versus 58.8%, p=0.015, pc=0.060), combined with increased relapse rate (54.1% versus 21.9%, p=0.019, pc=0.076). Position 245 (a cysteine/arginine dimorphism) appeared less influential in transplant outcomes, with a weak trend seen for beneficial outcomes in KIR2DL-C245 likely attributed to its association with KIR2DL1-P114. KIR2DL1-R245 in the donor was found to be neutral with no influence upon post-transplant outcomes. These findings provide proof of principle that position 114 of KIR2DL1 may be a viable donor selection mechanism, and confirms the proposition that KIR genomics should be assessed in the context of wider transplant conditioning protocols. A larger multi-centre study is recommended to verify results, and to assess the applicability in other transplant centres.

Date of Award	1 Aug 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Lynne Hampson (Supervisor)