title: Cross talk between follicular Th cells and tumor cells in human follicular lymphoma promotes immune evasion in the tumor microenvironment.
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 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.
authors.affiliation: Division of Cancer Medicine, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Seema
authors.initials: S
authors.lastname: Rawal
authors.forename: Fuliang
authors.initials: F
authors.lastname: Chu
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Hyun Jun
authors.initials: HJ
authors.lastname: Park
authors.forename: Durga
authors.initials: D
authors.lastname: Nattamai
authors.forename: Shibichakravarthy
authors.initials: S
authors.lastname: Kannan
authors.forename: Rakesh
authors.initials: R
authors.lastname: Sharma
authors.forename: David
authors.initials: D
authors.lastname: Delgado
authors.forename: Tina
authors.initials: T
authors.lastname: Chou
authors.forename: Heather Y
authors.initials: HY
authors.lastname: Lin
authors.forename: Veerabhadran
authors.initials: V
authors.lastname: Baladandayuthapani
authors.forename: Amber
authors.initials: A
authors.lastname: Luong
authors.forename: Francisco
authors.initials: F
authors.lastname: Vega
authors.forename: Nathan
authors.initials: N
authors.lastname: Fowler
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.forename: Sattva S
authors.initials: SS
authors.lastname: Neelapu
mesh_terms: D015153:Blotting, Western; D002469:Cell Separation; D054414:Chemokine CCL17 / Q000276:immunology / Q000378:metabolism; D054422:Chemokine CCL22 / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008224:Lymphoma, Follicular / Q000276:immunology* / Q000378:metabolism / Q000401:mortality; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D020239:Receptor Cross-Talk / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: C106230:CCL17 protein, human; C515482:CCL22 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D034741:RNA, Small Interfering