Treatment of superficial bladder cancer treated by resection plus adjuvant intravesical administration of bacille Calmette-Guérin (BCG) yields ≈60% to 70% remission rates; however, tumor recurrence does occur in more than half of patients. Unfortunately, there is no consensus for a predictive marker to assess response to BCG-based therapy. In a recent study, we found a humoral immune response against heat-shock protein (HSP65) from Mycobacterium bovis, a positive predictive marker of BCG immunotherapy.1 In another line of investigation, Cai et al recently demonstrated that a loss of heterozygosity (LOH) of IFN-α is linked to a poor outcome of BCG immunotherapy2; these results are in agreement with the hypothesis that the BCG effect is predominantly mediated by cellular immunity (eg, natural killer [NK] cells). In their insightful letter, Cai and Malossini propose an unrecognized, yet quite logical, connection between these related experimental findings: IFN-α is a potent activator of both cellular and humoral immune response. Thus, impairment of IFN-α function compromises both cellular immune response—leading to insufficient BCG response—as well as antibody production, as also observed in our study.1 Indeed, low antibody production against M. bovis BCG HSP65 may perhaps reflect insufficient immune activation caused by the LOH in the IFN-α loci, among other factors.
In our study, HSP65 was the predominant target of antibody production; however, several other stress response chaperones of the complex humoral antitumor immune response (such as HSP90) will most likely be present. Thus, one might speculate that BCG induces an anti-HSP immune response that may ultimately lead to elimination of tumor cells. HSPs are of particular interest because of their overexpression in tumor cells along with their antiapoptotic properties. Indeed, molecular mimicry between human and M. bovis HSP65 has been proposed as a mechanism of action.
In summary, the significance2 of IFN-α and our own data on antibody production against M. bovis BCG HSP65 to predict the outcome of BCG immunotherapy1 support the increasing evidence of a coactivation of humoral and cellular immunity induced by BCG.