B118
Association of the global HLA-DP supertype D-K with adverse outcome in childhood ALL suggests an unfavourable effect of glucocorticoid-induced regulatory T cells
Malcolm Taylor1, Rachel Wade2, Adiba Hussain1, Sue Richards2, Pamela Thompson1
1University of Manchester, UK, 2University of Oxford, UK
Background
We have reported that ~90% HLA-DPB1 alleles can be clustered into 6 supertypes (DP1-4, 6, 8), based on polymorphisms in 3 peptide pockets (1,4,6). A deficit of ALL patients with DP1 suggested that a DP1-restricted anti-leukaemic immune response may protect against ALL. Paradoxically, DP1 and DP3 were associated with poor event-free survival (EFS) in the UKALL XI childhood ALL trial. Since DP1 and DP3 have the same pocket 1 and 4 polymorphisms (aspartic acid-lysine; D-K), we compared EFS in UKALL XI patients with the D-K and non-D-K global supertypes.
Method
Remission blood samples obtained from ALL patients during the UK Childhood Cancer Study were typed for HLA-DPB1 alleles. DP supertypes (1-4,6,8) were assigned from peptide pocket amino acid polymorphisms. Patients in UKALL XI with global supertypes based on pocket 1 and 4 polymorphisms were stratified into D-K (DP1+DP3) and non-D-K (G-E [DP2], G-K [DP4] and D-E [DP6+DP8]), and EFS compared.
Results
Five (58.8%; 52.7-64.9 vs 67.3%; 63.4-71.2) and 10-year (55.2% 48.9-61.5 vs 64.5%;60.668.4) EFS were significantly worse (p=0.007) in D-K than non-D-K patients, respectively, with no significant difference between D-K homozygotes and heterozygotes. The frequency of D-K was increased in relapsed compared with non-relapsed patients (34.7% vs 29.0%; p=0.09), and EFS post-relapse was non-significantly reduced (p=0.2) in D-K compared to non-D-K patients (39.2% v 49.6% at 5 years).
Conclusion
Relapse risk was significantly greater in patients with the D-K (DP1+DP3) than non-D-K global supertype. Although the antigen binding to D-K is unknown, we suggest that it might be a leukaemia-associated onco-protein and that prednisolone therapy stimulated a glucocorticoid-induced regulatory (GITR+) T (Treg) cell response to this antigen in D-K patients, abrogating immune control of residual disease. To test this, we suggest that the Treg response in childhood ALL should be studied in detail.
