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Phenotype, functions and fate of adoptively transferred tumor draining lymphocytes activated ex vivo in mice with an aggressive weakly immunogenic mammary carcinoma.

AbstractBACKGROUND:
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.
AuthorsCatriona H T Miller, Laura Graham, Harry D Bear
JournalBMC immunology (BMC Immunol) Vol. 11 Pg. 54 (Nov 04 2010) ISSN: 1471-2172 [Electronic] England
PMID21050466 (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.)
Chemical References
  • Bryostatins
  • Ionomycin
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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