Cross talk between follicular Th cells and tumor cells in human follicular lymphoma promotes immune evasion in the tumor microenvironment

Seema Rawal, Fuliang Chu, Min Zhang, Hyun Jun Park, Durga Nattamai, Shibichakravarthy Kannan, Rakesh Sharma, David Delgado, Tina Chou, Heather Y. Lin, Veerabhadran Baladandayuthapani, Amber Luong, Francisco Vega, Nathan Fowler, Chen Dong, R. Eric Davis, Sattva S. Neelapu

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

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 T FH 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.

Original languageEnglish (US)
Pages (from-to)6681-6693
Number of pages13
JournalJournal of Immunology
Volume190
Issue number12
DOIs
StatePublished - Jun 15 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Rawal, S., Chu, F., Zhang, M., Park, H. J., Nattamai, D., Kannan, S., Sharma, R., Delgado, D., Chou, T., Lin, H. Y., Baladandayuthapani, V., Luong, A., Vega, F., Fowler, N., Dong, C., Davis, R. E., & Neelapu, S. S. (2013). Cross talk between follicular Th cells and tumor cells in human follicular lymphoma promotes immune evasion in the tumor microenvironment. Journal of Immunology, 190(12), 6681-6693. https://doi.org/10.4049/jimmunol.1201363