title: T-Cell Therapy Enabling Adenoviruses Coding for IL2 and TNFα Induce Systemic Immunomodulation in Mice With Spontaneous Melanoma.
abstract: 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 CD4CD25Foxp3 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.
authors.affiliation: *Cancer Gene Therapy Group, Department of Pathology, Faculty of Medicine, University of Helsinki §TILT Biotherapeutics Ltd ∥Department of Obstetrics and Gynecology ¶Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland †Skin Cancer Unit, German Cancer Research Center (DKFZ) ‡Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany.
authors.forename: Siri
authors.initials: S
authors.lastname: Tähtinen
authors.forename: Carolin
authors.initials: C
authors.lastname: Blattner
authors.forename: Markus
authors.initials: M
authors.lastname: Vähä-Koskela
authors.forename: Dipongkor
authors.initials: D
authors.lastname: Saha
authors.forename: Mikko
authors.initials: M
authors.lastname: Siurala
authors.forename: Suvi
authors.initials: S
authors.lastname: Parviainen
authors.forename: Jochen
authors.initials: J
authors.lastname: Utikal
authors.forename: Anna
authors.initials: A
authors.lastname: Kanerva
authors.forename: Viktor
authors.initials: V
authors.lastname: Umansky
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005822:Genetic Vectors / Q000235:genetics; D056747:Immunomodulation; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D047368:Tumor Burden; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D007376:Interleukin-2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D014409:Tumor Necrosis Factor-alpha; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human