T-cell therapy enabling adenoviruses coding for IL2 and TNFα induce systemic immunomodulation in mice with spontaneous melanoma
The immunosuppressive microenvironment of solid tumors renders adoptively transferred T cells hypofunctional. However, adenoviral delivery of immunostimulatory cytokines IL2 and TNFα can significantly improve the efficacy of adoptive T-cell therapy. Using ret transgenic mice that spontaneously devel...
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| Main Authors: | , , |
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| Other Authors: | |
| Format: | Article (Journal) |
| Language: | English |
| Published: |
November/December 2016
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| In: |
Journal of immunotherapy
Year: 2016, Volume: 39, Issue: 9, Pages: 343-354 |
| ISSN: | 1537-4513 |
| DOI: | 10.1097/CJI.0000000000000144 |
| Online Access: | Verlag, Volltext: https://doi.org/10.1097/CJI.0000000000000144 Verlag, Volltext: https://journals.lww.com/immunotherapy-journal/fulltext/2016/11000/T_Cell_Therapy_Enabling_Adenoviruses_Coding_for.2.aspx 
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| Author Notes: | Siri Tähtinen, Carolin Blattner, Markus Vähä-Koskela, Dipongkor Saha, Mikko Siurala, Suvi Parviainen, Jochen Utikal, Anna Kanerva, Viktor Umansky, and Akseli Hemminki |
| Summary: | The immunosuppressive microenvironment of solid tumors renders adoptively transferred T cells hypofunctional. However, adenoviral delivery of immunostimulatory cytokines IL2 and TNFα can significantly improve the efficacy of adoptive T-cell therapy. Using ret transgenic mice that spontaneously develop skin malignant melanoma, we analyzed the mechanism of action of adenoviruses coding for IL2 and TNFα in combination with adoptive transfer of TCR-transgenic TRP-2-specific T cells. Following T-cell therapy and intratumoral virus injection, a significant increase in antigen-experienced, tumor-reactive PD-1+ CD8+ T cells was seen in both cutaneous lesions and in metastatic lymph nodes. A reverse correlation between tumor weight and the number of tumor-reactive PD-1+ tumor-infiltrating lymphocytes (TILs) was observed, suggesting that these T cells could target and kill tumor cells. It is interesting to note that, local expression of cytokines did not affect intratumoral levels of T-regulatory cells (Tregs), which had previously been associated with systemic IL2 therapy. Instead, Ad5-IL2 induced upregulation of IL2 receptor α-chain (CD25) on conventional CD4+CD25+Foxp3− cells, indicating that these CD4+ T cells may contribute to CD8+ T-cell activation and/or homing. Signs of therapy-induced resistance were also observed as the expression of PD-L1 on tumor-infiltrating granulocytic myeloid-derived suppressor cells was upregulated as a reaction to PD-1+ TILs. Finally, beneficial ratios between tumor-reactive PD-1+ CD8+ TILs and immunosuppressive cell subsets (Tregs and nitric oxide-producing myeloid-derived suppressor cells) were observed in primary and secondary tumor sites, indicating that local delivery of IL2 and TNFα coding adenoviruses can systemically modify the cellular composition of the tumor microenvironment in favor of adoptively transferred T cells. |
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| Item Description: | Gesehen am 11.04.2019 |
| Physical Description: | Online Resource |
| ISSN: | 1537-4513 |
| DOI: | 10.1097/CJI.0000000000000144 |