Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction

Journal for ImmunoTherapy of Cancer

Pawel Kalinski³  Jeffrey R Gingrich²  Jamie Pitteroff¹  Liwen Wang¹  Ravikumar Muthuswamy¹ 

[1] Departments of Sugery, University of Pittsburgh, Pittsburgh 15213, PA, USA;Department of Urology, University of Pittsburgh, Pittsburgh 15213, PA, USA;Department of Surgery, University of Pittsburgh, Hillman Cancer Center, UPCI Research Pavilion, Room 1.46b, 5117 Center Avenue, Pittsburgh 15213, PA, USA

关键词: Regulatory T cells;    Effector T cells;    Bladder cancer;    IFNα;    Poly-I :C;    TLR3;    BCG;    Chemokines;    Immunomodulation;    Tumor microenvironment;   

Others  :  1144131
DOI  :  10.1186/s40425-015-0050-8

 received in 2014-11-24, accepted in 2015-02-16,  发布年份 2015

【 摘 要 】

Background

BCG 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.

Methods

Freshly 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.

Results

Bladder cancer tissues spontaneously expressed high levels of the granulocyte/MDSC-attractant CXCL8 and T_reg-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.

Conclusions

The 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.

【 授权许可】

   
2015 Muthuswamy et al.; licensee BioMed Central.

【 图 表 】

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