Khodadoust et al. employed modern technologies to find evidence for a "old" hypothesis while looking for novel therapeutically viable neoantigen targets. The researchers used an integrated genomic and proteomic approach to mantle cell lymphoma from 17 untreated patients to investigate the peptides presented by MHC class I and class II molecules, which are abundant on the tumor's surface. They discovered indications for increased optimism about the potential usefulness of idiotype vaccination targeting patient-specific lymphoma immunoglobulin (Ig).
Whole exome sequencing and focused sequencing of the rearranged lymphoma Ig revealed 13 to 175 somatic mutations per patient, the vast majority of which were unique to each patient. Almost half of the expressed genes with coding mutations (46%) contained at least one peptide on an MHC class I or II molecule. This shows that these altered proteins are actively processed by proteasomes. With the exception of Ig neoantigen peptides, none of the peptides reported were produced from mutant areas of any of these genes. Finally, 67 neoantigenic epitopes were identified, all of which were encoded by genes encoding Ig heavy- or light-chain variable sections.
All 17 patients had lymphoma Ig peptides displayed on MHC class I and class II molecules, however the antigen presentation patterns differed across the two MHC classes. The vast majority of the more than 200 Ig-derived MHC class I peptides discovered by mass spectrometry were from the constant domains, with only 21 from the heavy- and light-chain variable sections, and only one of them classified as "neoantigenic." In contrast, of the 499 Ig-derived MHC class II peptides identified, 147 were discovered in variable areas, with 66 of those being neoantigenic.
As the authors point out, the unanticipated bias against MHC class I presentation (despite the fact that strong binders from the variable region were predicted for MHC class I) supports immunoediting, although the precise mechanism is unknown. The relatively frequent presentation of variable-region peptides by MHC class II, on the other hand, shows that recognition by CD4+ cells does not impede, but rather promotes tumor growth. Ig neoantigen-specific T cells have been demonstrated to have a Th2/Th17-like phenotype, lending support to this notion.
The researchers examined peripheral blood samples from three individuals in search of T cells specific to these Ig-derived neoantigens and discovered them in one of the three samples studied. In this patient, autologous tumor cell immunization stimulated the growth of these neoantigen-specific T cell clones. After being activated and grown with autologous Ig neoepitopes, isolated CD4+ T cells from another patient displayed the ability to specifically detect and destroy the patient's own lymphoma cells.
This research implies that IgG neoantigens could be used as immunotherapy targets for lymphoma. Previous clinical trials held high hopes for the effectiveness of idiotype vaccines, but the findings were dismal. These new findings imply that MHC presentation of epitopes originating from different areas is not ubiquitous across individual lymphomas, increasing the prospect that this therapy may only be successful in patients who have Ig neoepitopes.
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