Journal Article

Comparison of Immunity in Mice Cured of Primary/Metastatic Growth of EMT6 or 4THM Breast Cancer by Chemotherapy or Immunotherapy

Khatri, Ismat, Podnos, Anna, Chen, Zhiqi, Gorczynski, Reginald M., Erin, Nuray

2014

Overview

We have compared cure from local/metastatic tumor growth in BALB/c mice receiving EMT6 or the poorly immunogenic, highly metastatic 4THM, breast cancer cells following manipulation of immunosuppressive CD200:CD200R interactions or conventional chemotherapy. We reported previously that EMT6 tumors are cured in CD200R1KO mice following surgical resection and immunization with irradiated EMT6 cells and CpG oligodeoxynucleotide (CpG), while wild-type (WT) animals developed pulmonary and liver metastases within 30 days of surgery. We report growth and metastasis of both EMT6 and a highly metastatic 4THM tumor in WT mice receiving iv infusions of Fab anti-CD200R1 along with CpG/tumor cell immunization. Metastasis was followed both macroscopically (lung/liver nodules) and microscopically by cloning tumor cells at limiting dilution in vitro from draining lymph nodes (DLN) harvested at surgery. We compared these results with local/metastatic tumor growth in mice receiving 4 courses of combination treatment with anti-VEGF and paclitaxel. In WT mice receiving Fab anti-CD200R, no tumor cells are detectable following immunotherapy, and CD4+ cells produced increased TNFα/IL-2/IFNγ on stimulation with EMT6 in vitro. No long-term cure was seen following surgery/immunotherapy of 4THM, with both microscopic (tumors in DLN at limiting dilution) and macroscopic metastases present within 14 d of surgery. Chemotherapy attenuated growth/metastases in 4THM tumor-bearers and produced a decline in lung/liver metastases, with no detectable DLN metastases in EMT6 tumor-bearing mice-these latter mice nevertheless showed no significantly increased cytokine production after restimulation with EMT6 in vitro. EMT6 mice receiving immunotherapy were resistant to subsequent re-challenge with EMT6 tumor cells, but not those receiving curative chemotherapy. Anti-CD4 treatment caused tumor recurrence after immunotherapy, but produced no apparent effect in either EMT6 or 4THM tumor bearers after chemotherapy treatment. Immunotherapy, but not chemotherapy, enhances CD4+ immunity and affords long-term control of breast cancer growth and resistance to new tumor foci.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Antibodies - therapeutic use / Antigens, CD - immunology / Antineoplastic Agents, Phytogenic - therapeutic use / Biology and Life Sciences / Breast cancer / Breast Neoplasms - pathology / Breast Neoplasms - surgery / Breast Neoplasms - therapy / Cancer / Cancer therapies / CD200 antigen / CD4 antigen / CD4 Antigens - immunology / CD4-Positive T-Lymphocytes - cytology / CD4-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - cytology / CD8-Positive T-Lymphocytes - immunology / Cell Line, Tumor / Chemotherapy / Cloning / Constraining / CpG islands / Cytotoxicity / Dilution / Experiments / Female / Gene expression / Health care networks / Hospitals / Humans / Immunity / Immunization / Immunogenicity / Immunoglobulin Fab Fragments - therapeutic use / Immunosuppression / Immunotherapy / Inflammation / Interferon-gamma - metabolism / Interleukin 2 / Interleukin-2 - metabolism / Liver / Liver Neoplasms - pathology / Liver Neoplasms - prevention & control / Liver Neoplasms - secondary / Lung Neoplasms - pathology / Lung Neoplasms - prevention & control / Lung Neoplasms - secondary / Lung nodules / Lungs / Lymph nodes / Lymph Nodes - pathology / Lymphocytes / Mammary Neoplasms, Experimental - pathology / Mammary Neoplasms, Experimental - surgery / Mammary Neoplasms, Experimental - therapy / Medicine and Health Sciences / Metastases / Metastasis / Mice / Mice, Inbred BALB C / Mice, Knockout / Neoplasm Recurrence, Local - prevention & control / Nodules / Oligodeoxyribonucleotides - immunology / Orexin Receptors - deficiency / Orexin Receptors - genetics / Orexin Receptors - metabolism / Paclitaxel / Paclitaxel - therapeutic use / Rodents / Spleen - cytology / Spleen - transplantation / Surgery / Transplantation, Homologous / Tumor cells / Tumor Necrosis Factor-alpha - metabolism / Tumor necrosis factor-α / Tumors / Vascular endothelial growth factor / γ-Interferon