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




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BMC Immunology

, 11:54

First Online: 04 November 2010Received: 11 January 2010Accepted: 04 November 2010

Abstract

BackgroundRegression 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.

ResultsAdoptive 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.

ConclusionsAdoptively transferred CD8+ CD62L 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.

AbbreviationsAbsantibodies

AITadoptive immunotherapy

ANOVAanalysis of variance

B-Ibryostatin and ionomycin

C-complement

CFDA-SECarboxyfluorescein Diacetate Succinimidyl Ester

CFSEcarboxyfluoroscein succinimidyl ester

cLNcontralateral lymph node

CTLcytotoxic T lymphocytes

CYPcyclophosphamide

DLNdraining lymph node

IFN-γInterferon-γ

IPintraperitoneal

IVintravenously

LCMVLymphocytic Choriomeningitis Virus

LMListeria monocytogenes

mAbmonoclonal antibody

PBMCperipheral blood mononuclear cells

TBHtumor bearing host

TCMcentral memory T cells

TcRT cell receptor

tDLNtumor draining lymph node

TEMeffector memory T cells

TregT regulatory cells

Tukey-s HSDTukey-Kramer honestly significant difference test.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2172-11-54 contains supplementary material, which is available to authorized users.

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Autor: Catriona HT Miller - Laura Graham - Harry D Bear

Fuente: https://link.springer.com/







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