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1.
J Immunol ; 190(12): 6681-93, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23686488

RESUMO

The microenvironment of human follicular lymphoma (FL), an incurable B cell non-Hodgkin's lymphoma, is thought to play a major role in its pathogenesis and course. Microenvironmental cells of likely importance include follicular Th cells (TFH) and regulatory T cells (Tregs), and understanding their interactions with FL tumor cells is necessary to develop novel therapeutic strategies. We found that IL-4 and CD40L are expressed by intratumoral TFH and induce production of CCL17 and CCL22 by FL tumor cells. IL-4 alone induces only CCL17 but enhances stimulation by CD40L of both CCL17 and CCL22. Consistent with our in vitro results, mRNA transcripts of IL-4 correlated with CCL17, but not CCL22, in gene expression profiling studies of FL biopsies, whereas CD40L correlated with both CCL17 and CCL22. Tumor supernatants induced preferential migration of Tregs and IL-4-producing T cells rather than IFN-γ-producing T cells, and Abs to CCR4 significantly abrogated the migration of Tregs. Our results suggest that through two distinct mechanisms, intratumoral TFH induce production of CCL17 and CCL22 by FL tumor cells and facilitate active recruitment of Tregs and IL-4-producing T cells, which, in turn, may stimulate more chemokine production in a feed-forward cycle. Thus, TFH appear to play a major role in generating an immunosuppressive tumor microenvironment that promotes immune escape and tumor survival and growth. Our results provide novel insights into the cross talk among TFH, tumor cells, and Tregs in FL, and offer potential targets for development of therapeutic strategies to overcome immune evasion.


Assuntos
Linfoma Folicular/imunologia , Receptor Cross-Talk/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia , Western Blotting , Separação Celular , Quimiocina CCL17/imunologia , Quimiocina CCL17/metabolismo , Quimiocina CCL22/imunologia , Quimiocina CCL22/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfoma Folicular/metabolismo , Linfoma Folicular/mortalidade , Análise de Sequência com Séries de Oligonucleotídeos , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real
2.
Int J Cancer ; 135(12): 2834-46, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24771328

RESUMO

Immunotherapeutic strategies are promising approaches for the treatment of follicular lymphoma (FL). However, their efficacy may be limited by immunosuppressive elements in the immune system and tumor microenvironment. Therefore, strategies to reverse the effects of the immunosuppressive elements are needed. We observed that regulatory T cells (Tregs) were increased in the peripheral blood at diagnosis and persisted in high numbers after induction of clinical remission with a cyclophosphamide and doxorubicin-containing chemotherapy regimen in FL patients. High levels of peripheral blood Tregs prior to therapy were associated with decreased progression-free survival in FL patients treated with either chemotherapy or combination immunotherapy that targeted CD20 and PD-1 with monoclonal antibodies rituximab and pidilizumab, respectively. Intratumoral and peripheral blood Tregs potently suppressed autologous antitumor effector T cells in FL. However, the effects of FL Tregs could be reversed by triggering Toll-like receptors (TLR) with TLR ligands Pam3 CSK4 (TLR 1/2), flagellin (TLR 5), and CpG-B (TLR 9), and/or OX40. The TLR ligands synergized with each other as well as OX40 signaling to inhibit Tregs. Furthermore, they restored the function of FL tumor-specific effector T cells. Our results suggest that a state of tolerance exists in FL patients at diagnosis and after induction of clinical remission, and agents that activate TLRs 1/2, 5, and 9, and OX40 may serve as adjuvants to enhance the efficacy of antitumor immunotherapeutic strategies and preventive vaccines against infectious diseases in these patients.


Assuntos
Regulação Neoplásica da Expressão Gênica , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/metabolismo , Receptores OX40/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Receptores Toll-Like/metabolismo , Adulto , Idoso , Antígenos CD20/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Separação Celular , Ciclofosfamida/farmacologia , Intervalo Livre de Doença , Doxorrubicina/farmacologia , Feminino , Citometria de Fluxo , Humanos , Imunossupressores/farmacologia , Imunoterapia/métodos , Interleucina-10/metabolismo , Ligantes , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Indução de Remissão , Linfócitos T Reguladores/citologia , Resultado do Tratamento , Adulto Jovem
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