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 lymphomas escape Id-specific killer T cells: does this preclude Id vaccination? Recent in silico findings by Veelken and coworkers suggest that B lymphoma–derived Ig V-region Id peptides bind poorly to the patient's own HLA class I molecules, indicating that only lymphoma cells which escape immunosurveillance by Id-specific CD8+ T cells progress into clinical cancers.2  Nevertheless, they now show that Id vaccination of patients can elicit Id-specific responses including CD8+ responses.1  These results indicate that B-lymphoma patients are not totally devoid of lymphoma-reactive Id-specific CD8+ T cells and that these can be stimulated by vaccination with patient Fab fragments produced in bacteria. (Professional illustration by Paulette Dennis.)

B lymphomas escape Id-specific killer T cells: does this preclude Id vaccination? Recent in silico findings by Veelken and coworkers suggest that B lymphoma–derived Ig V-region Id peptides bind poorly to the patient's own HLA class I molecules, indicating that only lymphoma cells which escape immunosurveillance by Id-specific CD8+ T cells progress into clinical cancers.2  Nevertheless, they now show that Id vaccination of patients can elicit Id-specific responses including CD8+ responses.1  These results indicate that B-lymphoma patients are not totally devoid of lymphoma-reactive Id-specific CD8+ T cells and that these can be stimulated by vaccination with patient Fab fragments produced in bacteria. (Professional illustration by Paulette Dennis.)

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 Ig3,4  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.

Conflict-of-interest disclosure: The author declares no competing financial interests. ■

1
Navarrete
 
MA
Heining-Mikesch
 
K
Schüler
 
F
, et al. 
Upfront immunization with autologous recombinant idiotype Fab fragment without prior cytoreduction in indolent B-cell lymphoma.
Blood
2011
, vol. 
117
 
5
(pg. 
1483
-
1491
)
2
Strothmeyer
 
AM
Papaioannou
 
D
Duhren-von Minden
 
M
, et al. 
Comparative analysis of predicted HLA binding of immunoglobulin idiotype sequences indicates T cell-mediated immunosurveillance in follicular lymphoma.
Blood
2010
, vol. 
116
 
10
(pg. 
1734
-
1736
)
3
Stevenson
 
FK
George
 
AJ
Glennie
 
MJ
Anti-idiotypic therapy of leukemias and lymphomas.
Chem Immunol
1990
, vol. 
48
 (pg. 
126
-
166
)
4
Levy
 
R
Miller
 
RA
Therapy of lymphoma directed at idiotypes.
J Natl Cancer Inst Monogr
1990
, vol. 
10
 (pg. 
61
-
68
)
5
Lauritzsen
 
GF
Weiss
 
S
Dembic
 
Z
Bogen
 
B
Naive idiotype-specific CD4+ T cells and immunosurveillance of B-cell tumors.
Proc Natl Acad Sci U S A
1994
, vol. 
91
 
12
(pg. 
5700
-
5704
)
6
Armstrong
 
AC
Dermime
 
S
Allinson
 
CG
, et al. 
Immunization with a recombinant adenovirus encoding a lymphoma idiotype: induction of tumor-protective immunity and identification of an idiotype-specific T cell epitope.
J Immunol
2002
, vol. 
168
 
8
(pg. 
3983
-
3991
)
7
Bendandi
 
M
Idiotype vaccines for lymphoma: proof-of-principles and clinical trial failures.
Nat Rev Cancer
2009
, vol. 
9
 
9
(pg. 
675
-
681
)
8
Zangani
 
MM
Froyland
 
M
Qiu
 
GY
, et al. 
Lymphomas can develop from B cells chronically helped by idiotype-specific T cells.
J Exp Med
2007
, vol. 
204
 
5
(pg. 
1181
-
1191
)
9
Ostad
 
M
Andersson
 
M
Gruber
 
A
Sundblad
 
A
Expansion of immunoglobulin autoreactive T-helper cells in multiple myeloma.
Blood
2008
, vol. 
111
 
5
(pg. 
2725
-
2732
)