Abstract
A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4). However, the determinants of response to anti-CTLA-4 mAb treatment remain incompletely understood. In murine models, anti-CTLA-4 mAbs alone fail to induce effective immune responses to poorly immunogenic tumors but are successful when combined with additional interventions, including local ionizing radiation (IR) therapy. We employed an established model based on control of a mouse carcinoma cell line to study endogenous tumor-infiltrating CD8+ T lymphocytes (TILs) following treatment with the anti-CTLA-4 mAb 9H10. Alone, 9H10 monotherapy reversed the arrest of TILs with carcinoma cells in vivo. In contrast, the combination of 9H10 and IR restored MHC class I-dependent arrest. After implantation, the carcinoma cells had reduced expression of retinoic acid early inducible-1 (RAE-1), a ligand for natural killer cell group 2D (NKG2D) receptor. We found that RAE-1 expression was induced by IR in vivo and that anti-NKG2D mAb blocked the TIL arrest induced by IR/9H10 combination therapy. These results demonstrate that anti-CTLA-4 mAb therapy induces motility of TIL and that NKG2D ligation offsets this effect to enhance TILs arrest and antitumor activity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology
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Antibodies, Monoclonal / therapeutic use*
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CD8-Positive T-Lymphocytes / drug effects*
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / radiation effects
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CTLA-4 Antigen / antagonists & inhibitors*
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Cell Line, Tumor / immunology
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Cell Line, Tumor / transplantation
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Cell Movement
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Combined Modality Therapy
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Cytotoxicity, Immunologic / drug effects
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Cytotoxicity, Immunologic / radiation effects
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Drug Screening Assays, Antitumor
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / radiation effects
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H-2 Antigens / immunology
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Immunotherapy*
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Intercellular Adhesion Molecule-1 / biosynthesis
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Intercellular Adhesion Molecule-1 / genetics
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Lymphocytes, Tumor-Infiltrating / drug effects*
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Lymphocytes, Tumor-Infiltrating / immunology
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Lymphocytes, Tumor-Infiltrating / radiation effects
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Mammary Neoplasms, Experimental / immunology
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Mammary Neoplasms, Experimental / radiotherapy
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Mammary Neoplasms, Experimental / secondary
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Mammary Neoplasms, Experimental / therapy*
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Mice
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Mice, Inbred BALB C
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NK Cell Lectin-Like Receptor Subfamily K / antagonists & inhibitors
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NK Cell Lectin-Like Receptor Subfamily K / immunology
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Nuclear Matrix-Associated Proteins / biosynthesis
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Nuclear Matrix-Associated Proteins / genetics
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Nucleocytoplasmic Transport Proteins / biosynthesis
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Nucleocytoplasmic Transport Proteins / genetics
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Receptors, CXCR / genetics
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Receptors, CXCR6
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Tumor Microenvironment / immunology
Substances
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Antibodies, Monoclonal
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CTLA-4 Antigen
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Cxcr6 protein, mouse
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H-2 Antigens
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Icam1 protein, mouse
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Klrk1 protein, mouse
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NK Cell Lectin-Like Receptor Subfamily K
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Neoplasm Proteins
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Nuclear Matrix-Associated Proteins
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Nucleocytoplasmic Transport Proteins
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Rae1 protein, mouse
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Receptors, CXCR
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Receptors, CXCR6
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Intercellular Adhesion Molecule-1