Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7–1 (CD80) and only a subset express B7–2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7–1 and B7–2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.

The above story illustrates the translation of basic scientific discoveries to the clinic. In vitro and preclinical in vivo experimentation suggests that modulation of the B7:CD28 pathway will result in either amplification or suppression of the immune response. Considering the frequency with which diseases characterized by either inadequate or dysregulated immune function present to the practicing hematologist or oncologist, it is not difficult to envisage clinical applications for reagents that modulate this pathway. However, we still have much to learn about the function and clinical potential of this and other potentially redundant costimulatory pathways and therefore we suspect that this story will become considerably more complex over the next few years.

CD44 exists in a variety of alternatively spliced isoforms that include variable numbers of additional exons from the membrane proximal domain (exons 6–14). Lymphocytes express high levels of a “hematopoietic” isoform (CD44H) with no additional variable exons. CD44H binds lymphocytes to postcapillary venules and promotes lymphocyte extravasation into nodal areas. Epithelial carcinomas also express CD44 variants, including exon 10-containing isoforms associated with metastasis in a rat model. An exon 10-containing CD44 isoform is also transiently expressed by normal activated lymphocytes, suggesting that the protein may function in the trafficking of both normal lymphocytes and metastatic tumors. To identify the specific CD44 transcripts in tumors from patients with primary nodal, extranodal, and disseminated large-cell lymphomas (LCLs) and compare them with CD44 mRNAs in normal Ig-activated splenic B cells and epithelial cells, we used a semiquantitative RNA-based polymerase chain reaction. Specific CD44 variants were identified by size, hybridization with exon-specific probes, and sequence analysis. In comparison to primary nodal LCLs, extranodal and disseminated LCLs had increased levels of CD44H and additional isoforms, including a directly spliced (exon 5-->exon 10-- >exon 15) exon 10-containing CD44 variant. The CD44 transcripts in extranodal and advanced-stage LCLs were similar to those in normal Ig- activated splenic B cells, whereas epithelial malignancies contained decreased CD44H and increased amounts of larger CD44 variants with additional exons from the membrane proximal domain. The regulated expression of specific CD44 variants is likely to influence the trafficking of lymphoid and epithelial malignancies.