Ag-Specific Type 1 CD8 Effector Cells Enhance Methotrexate-Mediated Antitumor Responses by Modulating Endogenous CD49b-Expressing CD4 and CD8 T Effector Cell Subpopulations Producing IL-10

• Published in: Immunological investigations Vol. 37; no. 4; pp. 315 - 338
• Main Authors: Dobrzanski, Mark J., Reome, Joyce B., Hylind, James C., Rewers-Felkins, Kathleen A., Abdulsamad, Khaliquzzaman, Adams, Shawna L.
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 01-01-2008; Taylor & Francis
• Subjects: Adenocarcinoma - immunology; Adenocarcinoma - therapy; Adoptive Transfer; Animals; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - pharmacology; Cell Line, Tumor; Chemotherapy; Combined Modality Therapy; Cytokines; Female; IL-10; Immunoregulatory cells; Integrin alpha2 - immunology; Integrin alpha2 - metabolism; Interleukin-10 - immunology; Interleukin-10 - metabolism; Mammary Neoplasms, Animal - immunology; Mammary Neoplasms, Animal - therapy; Methotrexate - administration & dosage; Methotrexate - pharmacology; Mice; Mice, Inbred BALB C; Mice, Transgenic; T effector/memory cells; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Tc1/Th1 cells; Tumor immunity
• ISSN: 0882-0139; 1532-4311
• DOI: 10.1080/08820130802083762

The chemotherapeutic agent methotrexate is widely used in the treatment of breast cancer. Although its mechanism-of-action has been defined, less is known about its interaction with Ag-specific T cell-mediated antitumor responses. Type 1 CD8 T cell-mediated immune responses (Tc1) are cytolytic, produce IFN-gamma and are associated with effective antitumor responses. Using a murine transgenic TCR tumor model, we show that single-dose-treatment with methotrexate enhanced CD8-mediated type 1 antitumor responses when administered three days prior to Tc1 effector cell transfer. Co-treatment with methotrexate not only enhanced donor Tc1 cell accumulation and persistence at sites of primary tumor growth, but also promoted elevated levels of activated CD25+ expressing donor TIL cells. This correlated with a marked decrease in the appearance of endogenous differentiated (CD44High) CD3 CD8 CD49b and CD3 CD4 CD49b tumor-infiltrating effector T cells at both early (Days 1-8) and late (Days 12-20) stages following treatment when compared to that of corresponding groups receiving either MTX or Tc1 cell transfer alone. Moreover, such cellular response kinetics appeared to further correlate with the down-regulation of endogenous CD4 CD44High CD49b effector T cells producing IL-10 and delays in tumor growth in vivo. This suggested that Ag-specific Tc1 cell transfer, in combination with chemotherapy, can enhance antitumor responses by modulating select CD49b-expressing T effector memory cell subpopulations involved in homeostasis and immune tolerance within the tumor environment. These studies offer insight into mechanisms that enhance T cell-based immunotherapy in cancer. Supplementary materials are available for this article. Go to the publisher's online edition of Immunological Investigations for the following free supplemental resource(s): Addendum 1.