Abstract | BACKGROUND: Regression of established tumors can be induced by adoptive immunotherapy with tumor draining lymph node lymphocytes activated with bryostatin and ionomycin. We hypothesized that tumor regression is mediated by a subset of the transferred T lymphocytes, which selectively infiltrate the tumor draining lymph nodes and proliferate in vivo. RESULTS: Adoptive transfer of B/I activated tumor draining lymphocytes induces regression of advanced 4T1 tumors, and depletion of CD8, but not CD4 T cells, abrogated tumor regression in mice. The predominant mediators of tumor regression are CD8+ and derived from CD62L- T cells. Transferred lymphocytes reached their peak concentration (10.5%) in the spleen 3 days after adoptive transfer and then rapidly declined. Adoptively transferred cells preferentially migrated to and/or proliferated in the tumor draining lymph nodes, peaking at day 5 (10.3%) and remained up to day 28. CFSE-stained cells were seen in tumors, also peaking at day 5 (2.1%). Bryostatin and ionomycin-activated cells proliferated vigorously in vivo, with 10 generations evident in the tumor draining lymph nodes on day 3. CFSE-stained cells found in the tumor draining lymph nodes on day 3 were 30% CD8+, 72% CD4+, 95% CD44+, and 39% CD69+. Pre-treatment of recipient mice with cyclophosphamide dramatically increased the number of interferon-gamma producing cells. CONCLUSIONS: Adoptively transferred CD8+ CD62L(low) T cells are the principal mediators of tumor regression, and host T cells are not required. These cells infiltrate 4T1 tumors, track preferentially to tumor draining lymph nodes, have an activated phenotype, and proliferate in vivo. Cyclophosphamide pre-treatment augments the anti- tumor effect by increasing the proliferation of interferon-gamma producing cells in the adoptive host.
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Authors | Catriona H T Miller, Laura Graham, Harry D Bear |
Journal | BMC immunology
(BMC Immunol)
Vol. 11
Pg. 54
(Nov 04 2010)
ISSN: 1471-2172 [Electronic] England |
PMID | 21050466
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
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Topics |
- Animals
- Breast Neoplasms
(immunology, pathology, therapy)
- Bryostatins
(pharmacology)
- CD8-Positive T-Lymphocytes
(drug effects, immunology, metabolism, pathology)
- Carcinoma
(immunology, pathology, therapy)
- Cell Movement
(immunology)
- Cell Proliferation
(drug effects)
- Immunophenotyping
- Immunotherapy, Adoptive
- Ionomycin
(pharmacology)
- Lymph Nodes
(pathology)
- Lymphocyte Activation
(drug effects)
- Lymphocytes, Tumor-Infiltrating
(pathology)
- Mice
- Neoplasm Regression, Spontaneous
- Neoplasm Transplantation
- Tumor Escape
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