Lymphoma invisibility–vaccination–attack?

In this issue of Blood, Navarrete et al report that upfront immunization of follicular B-cell lymphoma patients with bacterially produced Fab fragments induces immune responses; however, the influence on patient outcome is not yet known.¹ 

These results should be discussed together with a recent study in Blood by the Veelken laboratory.²  The authors suggest that B lymphomas escape killing by idiotype-specific CD8⁺ T cells, simply because the relevant parts of their immunoglobulin (Ig) V-region sequences bind poorly to the patient's own human leukocyte antigen (HLA) class I molecules.²  Taken together, these results indicate that even though the B lymphoma is relatively invisible to the patient's killer T cells, such cytotoxic cells can nevertheless be stimulated by vaccination to become responsive to lymphoma Ig (see figure).

B-lymphoma cells express an exquisite tumor-specific antigen, monoclonal Ig, which contains unique antigenic determinants called idiotopes (Id) in their variable (V) regions. An immune attack against Id on the B-lymphoma cells could take 2 forms: (1) anti-idiotypic antibodies binding the surface Ig^3,4  and (2) T cells recognizing short V region–derived Id peptides presented on the lymphoma's HLA molecules.^5,6  Major efforts have been made by numerous investigators to generate individualized Id vaccines that elicit clinically meaningful immune attacks against lymphomas, but the results have been mixed.⁷ 

The finding that Ig V regions of lymphomas bind poorly to the patients' own HLA class I molecules, as analyzed by bioinformatics, indicates that emerging B-lymphoma cells must escape an otherwise effective immune attack by Id-specific CD8⁺ killer T cells. This finding extends previous observations demonstrating that Id-specific CD4⁺ T cells play a role in immunosurveillance of B lymphomas.⁵  Thus, clinical B lymphomas may already be immune-sculpted into having an invisibility cloak, which suggests that Id vaccination could be futile simply because the patient's B lymphoma has been selected to escape an immune attack. A counterargument is that Id vaccination could boost otherwise too weak T-cell reactivity so that it rises to clinically relevant levels. In support of this idea, Navarrete and coworkers report in this issue that upfront Id vaccination of untreated patients with B lymphomas can elicit both Id-specific CD4⁺ and CD8⁺ T-cell responses, consistent with an available repertoire of weakly Id-reactive T cells that apparently can be boosted by vaccination (see figure).

Most investigators in this field would be inclined to believe that Id-specific T cells serve to eradicate B-lymphoma cells. However, it might be that some types of Id-specific T cells could have the opposite role and, in fact, support the growth of lymphomas. Indeed, previous reports have shown that Id-specific Th2 cells could induce Id⁺ B lymphomas in mice,⁸  and that Id-specific CD4⁺ T cells may play a role in development of multiple myeloma in humans.⁹  With some hindsight, such findings are perhaps not so surprising as helper T cells are known to induce proliferation of B cells, which in turn could predispose for oncogenetic mutations.

In broader terms, the many distinct subsets of T cells could differ in their effect on B-lymphoma cells. Based on current immunologic wisdom, it is reasonable to suggest that Id-specific CD8⁺ T cells should kill B lymphomas, as suggested by the reports of Veelken and coworkers, while the roles of Th1, Th2, Th17, T follicular helper, and regulatory T cells remain to be firmly established. Given that different modes of Id vaccination could differ in their propensity to generate the various T-cell subsets, it is important to develop Id vaccines that elicit T-cell subsets with detrimental rather than supportive effects on B-lymphoma growth.