Detection of intra-tumor self antigen recognition during melanoma tumor progression in mice using advanced multimode confocal/two photon microscope

• Published in: PloS one Vol. 6; no. 6; p. e21214
• Main Authors: Schaer, David A, Li, Yongbiao, Merghoub, Taha, Rizzuto, Gabrielle A, Shemesh, Amos, Cohen, Adam D, Li, Yanyun, Avogadri, Francesca, Toledo-Crow, Ricardo, Houghton, Alan N, Wolchok, Jedd D
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.06.2011; Public Library of Science (PLoS)
• Subjects: Adenosine; Adoptive Transfer; Animals; Anticancer properties; Antigens; Antigens, Neoplasm - immunology; Autoantigens; Autoantigens - immunology; Biology; Cancer; CD8 antigen; Cell Communication; Cell Proliferation; Confocal; Cytotoxicity; Disease Progression; Engineering; Epitopes - immunology; Fluorescence; Health aspects; Imaging techniques; Immune response; Immune system; Immunity; Immunology; Immunosuppression; Killing; Kinetics; Laboratories; Lymphatic system; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - pathology; Medical research; Medicine; Melanoma; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Mice; Mice, Inbred C57BL; Microscopy; Microscopy, Confocal - methods; Mobility; Recognition; Reflectance; Regression analysis; Regulation; T cell receptors; T cells; T-Lymphocytes, Cytotoxic - immunology; Time Factors; Trends; Tumor cells; Tumors; γ-Interferon; New York; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0021214

Determining how tumor immunity is regulated requires understanding the extent to which the anti-tumor immune response "functions" in vivo without therapeutic intervention. To better understand this question, we developed advanced multimodal reflectance confocal/two photon fluorescence intra-vital imaging techniques to use in combination with traditional ex vivo analysis of tumor specific T cells. By transferring small numbers of melanoma-specific CD8+ T cells (Pmel-1), in an attempt to mimic physiologic conditions, we found that B16 tumor growth alone was sufficient to induce naive Pmel-1 T cell proliferation and acquisition of effector phenotype. Tumor -primed Pmel-1 T cells, are capable of killing target cells in the periphery and secrete IFNγ, but are unable to mediate tumor regression. Within the tumor, Pmel-1 T cells have highly confined mobility, displaying long term interactions with tumor cells. In contrast, adoptively transferred non tumor-specific OT-I T cells show neither confined mobility, nor long term interaction with B16 tumor cells, suggesting that intra-tumor recognition of cognate self antigen by Pmel-1 T cells occurs during tumor growth. Together, these data indicate that lack of anti-tumor efficacy is not solely due to ignorance of self antigen in the tumor microenvironment but rather to active immunosuppressive influences preventing a protective immune response.