Abstract
BackgroundBCG is a prototypal cancer immunotherapeutic factor currently approved of bladder cancer. In attempt to further enhance the effectiveness of immunotherapy of bladder cancer and, potentially, other malignancies, we evaluated the impact of BCG on local production of chemokines attracting the desirable effector CD8+ T cells (CTLs) and undesirable myeloid-derived suppressor cell (MDSCs) and regulatory T(reg) cells, and the ability of bladder cancer tissues to attract CTLs.MethodsFreshly resected bladder cancer tissues were either analyzed immediately or cultured ex vivo in the absence or presence of the tested factors. The expression of chemokine genes, secretion of chemokines and their local sources in freshly harvested and ex vivo-treated tumor explants were analyzed by quantitative PCR (Taqman), ELISAs and immunofluorescence/confocal microscopy. Migration of CTLs was evaluated ex vivo, using 24-transwell plates. Spearman correlation was used for correlative analysis, while paired Students T test or Wilcoxon was used for statistical analysis of the data.ResultsBladder cancer tissues spontaneously expressed high levels of the granulocyte/MDSC-attractant CXCL8 and Treg-attractant CCL22, but only marginal levels of the CTL-attracting chemokines: CCL5, CXCL9 and CXCL10. Baseline CXCL10 showed strong correlation with local expression of CTL markers. Unexpectedly, BCG selectively induced only the undesirable chemokines, CCL22 and CXCL8, but had only marginal impact on CXCL10 production. In sharp contrast, the combination of IFNα and a TLR3 ligand, poly-I:C (but not the combinations of BCG with IFNα or BCG with poly-I:C), induced high levels of intra-tumoral production of CXCL10 and promoted CTL attraction. The combination of BCG with IFNα + poly-I:C regimen did not show additional advantage.ConclusionsThe current data indicate that suboptimal ability of BCG to reprogram cancer-associated chemokine environment may be a factor limiting its therapeutic activity. Our observations that the combination of BCG with (or replacement by) IFNα and poly-I:C allows to reprogram bladder cancer tissues for enhanced CTL entry may provide for new methods of improving the effectiveness of immunotherapy of bladder cancer, helping to extend BCG applications to its more advanced forms, and, potentially, other diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-015-0050-8) contains supplementary material, which is available to authorized users.
Highlights
BCG is a prototypal cancer immunotherapeutic factor currently approved of bladder cancer
Prompted by the above considerations, we evaluated the ability of BCG and alternative adjuvants to reprogram local chemokine milieu in bladder cancer to enhance the overall magnitude of local production of CTLattracting chemokines in relation to MDSC/Treg-attractants
Bladder cancer tissues spontaneously produce MDSC- and Treg-attracting CXCL8 and CCL22, but not effector T cell-attracting chemokines In order to evaluate the spontaneous chemokine expression and determine the baseline chemokine production pattern in bladder tumors, we isolated RNA from resected tumors of bladder cancer patients (N = 20) and performed real-time PCR (Taqman) analysis for the chemokines previously implicated in CTL or MDSC/Treg attraction to tumor lesions [26,27,28,29,30]
Summary
BCG is a prototypal cancer immunotherapeutic factor currently approved of bladder cancer. Tumor infiltration with effector CD8+ T cells (CTL) has been associated with good prognosis in various cancers [5,6,7,8,9,10,11,12,13,14,15,16,17,18], immunotherapies able of enhancing intra-tumoral CTL levels may be effective for invasive bladder cancers. We observed that BCG, used alone, failed to enhance local expression of CTLattracting chemokines, CCL5 and CXCL10, but selectively enhanced MDSC- and Treg-attracting chemokines, CCL22 and CXCL8 These undesirable side-effects could be reversed by the combination of IFNα and polyI:C (TLR3 ligand), raising the possibility of enhancing the effectiveness of the BCG-based and other forms of immunotherapy of bladder cancer and potentially other malignancies
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
