Sarcoma Eradication by Doxorubicin and Targeted TNF Relies upon CD8 + T-cell Recognition of a Retroviral Antigen

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 13; pp. 3644 - 3654
• Main Authors: Probst, Philipp, Kopp, Janine, Oxenius, Annette, Colombo, Mario P, Ritz, Danilo, Fugmann, Tim, Neri, Dario
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 01.07.2017
• Subjects: Animals; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell recognition; Cytotoxicity; Doxorubicin; Doxorubicin - pharmacology; Female; Fibronectin; Fibrosarcoma; Histocompatibility antigen H-2; Humans; Immunosurveillance; Isoforms; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred BALB C; Retroviridae - immunology; Sarcoma; Sarcoma - drug therapy; Sarcoma - immunology; Sarcoma - pathology; T cell receptors; Tumor cell lines; Tumor cells; Tumor necrosis factor; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-2946

Antibody-cytokine complexes may offer new tools to treat cancer. Here, we show how TNF-linked antibodies, which recognize tumor-selective splice isoforms of fibronectin (F8-TNF), can be exploited to eradicate sarcomas in immunocompetent mice. We treated mice bearing WEHI-164 fibrosarcoma with a combination of F8-TNF and doxorubicin, curing the majority of treated animals (29/37). Notably, cured mice were resistant to rechallenge not only by WEHI-164 cells but also heterologous C51 or CT26 colorectal tumor cells in a CD8 T-cell-dependent process. Mechanistic analyses revealed that each tumor cell line presented AH1, a common endogenous retroviral peptide. Numbers of AH1-specific CD8 T cells exhibiting cytotoxic capacity were increased by F8-TNF plus doxorubicin treatment, arguing that cognate CD8 T cells contributed to tumor eradication. Sequence analysis of T-cell receptors of CD8 T cells revealed the presence of H-2L /AH1-specific T cells and an expansion of sequence diversity in treated mice. Overall, our findings provide evidence that retroviral genes contribute to tumoral immunosurveillance in a process that can be generally boosted by F8-TNF and doxorubicin treatment. .