Comparative analysis of predicted HLA binding of immunoglobulin idiotype sequences indicates T cell–mediated immunosurveillance in follicular lymphoma

Abstract

Active immunization with the idiotype of follicular lymphoma induces tumor-specific immunity. T cells induced in vivo by idiotype vaccination recognize human leukocyte antigen (HLA)-restricted hypervariable but not conserved idiotype peptides. We hypothesized that idiotype-directed T-cell immunity occurs naturally and performed a reverse immunology analysis of idiotype HLA binding in 39 follicular lymphoma patients. For every idiotype, the sum of HLA-A or -B binding scores of the 20 highest-scoring peptides was calculated for all 39 HLA types through the BIMAS algorithm. The idiotype sum score of every patient's lymphoma was compared on the respective patient's HLA type to the mean of the sum scores of the remaining 38 idiotypes. Autologous idiotypes had lower immunogenicity than allogeneicidiotypes.Differentialimmunogenicity resided predominantly in all 3 complementarity-determining regions rather than in framework peptides. IntroductionThe individual composition of potentially immunogenic epitopes of any immunoglobulin is designated as "idiotype." The idiotype is a unique feature for every B-cell clone and a tumor-specific antigen in B-cell lymphoma. Immunization of patients with follicular lymphoma (FL) against their lymphoma idiotype induces tumorspecific immunity. 1-3 When idiotype vaccination is administered as remission consolidation after conventional chemotherapy, humoral immune responses correlate with superior outcome. [4][5][6] Idiotype-specific, major histocompatibility complex (MHC) class I-restricted cytotoxic T cells circulate in lymphoma-bearing patients. 7 Immunization with recombinant idiotype F ab fragments induces idiotype-directed T cells in the majority of patients. 8,9 In the first trial testing idiotype vaccination as upfront intervention without prior cytoreductive therapy, anti-idiotype T-cell responses correlated with superior progression-free survival and with durable lymphoma remissions. 9 Peptide mapping experiments revealed that these T-cell responses are consistently directed against human leukocyte antigen (HLA) class I-restricted peptides from the complementarity-determining regions (CDRs) or against hypermutated idiotype epitopes. 8,9 These findings are in accordance with animal studies demonstrating T-cell tolerance for germlineencoded immunoglobulin sequences but responsiveness to novel idiotopes arising from junctional diversity or somatic mutations. 10 Because mouse models have also shown T cell-mediated immunosurveillance against hypervariable idiotypic peptides, 11 we sought to obtain evidence that spontaneous idiotype-directed T-cell immunity is operational in nonimmunized lymphoma patients and impairs expansion of malignant B-cell clones that express an idiotype with high immunogenicity. To test this hypothesis, we performed a "reverse immunology" bioinformatics study in 39 FL patients. Methods PatientsThe study was approved by the institutional ethics committee of University Medical Center Freiburg. All patients provided informed consent for biopsies and immunologic ...

Upfront immunization with autologous recombinant idiotype Fab fragment without prior cytoreduction in indolent B-cell lymphoma

“…45 We have recently presented bioinformatic evidence for selection of a given FL idiotype for relatively low immunogenicity by the affected patient's HLA type. 17 Although these findings may be taken as evidence for potential spontaneous antilymphoma T-cell activity against HLA class I-presented idiotype epitopes, our current data suggest that active idiotype immunization may convert an apparently inefficient immune recognition of intermediately immunogenic individual idiotypes into a clinically efficacious T-cell response. In this context, it may be a potentially important observation that the fraction of circulating Tregs, the most important cell population to maintain peripheral tolerance, 46 decreased in all analyzed patients.…”

“…We have recently presented indirect, "reverse immunology" evidence for T cell-mediated immunosurveillance against the idiotype of follicular lymphomas. 17 These results permit to speculate that subclinical T-cell reactivity that was insufficient to control lymphoma growth could be enhanced by active immunotherapy to exert clinically meaningful antilymphoma activity.…”

Evidence for idiotype-directed immunosurveillance is restricted to follicular lymphoma and attributable to somatic hypermutation

“…We have previously found evidence for HLA class I-dependent, BCR-directed immunosurveillance in follicular lymphoma (FL). 1 We here report lack of evidence for this mechanism in other indolent B-cell lymphomas and an apparent dependence of possible immunosurveillance on the high SHM rate in FL.…”

1086 IGHV1-69 as a Promising Candidate for the Development of a Shared Immunotherapy to B-cell Lymphomas

“…To do so, we excluded the hypervariable CDR3 region. In fact, even if this sequence's portion is often a carrier of immunogenic epitopes [126], it is primarily responsible for sequence variability and thus involved in the individualized character of current Id vaccinations. Moreover, most of NHLs considered in this study, derived from antigen-experienced B cells, whose Id proteins may carry somatic mutations, especially in the CDR3 region, that could possibly affect immune recognition [56].…”