A Preclinical Model for the ATLL Lymphoma Subtype With Insights Into the Role of Microenvironment in HTLV-1-Mediated Lymphomagenesis

Abstract

Adult T cell Leukemia/Lymphoma (ATLL) is a mature T cell malignancy associated with Human T cell Leukemia Virus type 1 (HTLV-1) infection. Among its four main clinical subtypes, the prognosis of acute and lymphoma variants remains poor. The long latency (3–6 decades) and low incidence (3–5%) of ATLL imply the involvement of viral and host factors in full-blown malignancy. Despite multiple preclinical and clinical studies, the contribution of the stromal microenvironment in ATLL development is not yet completely unraveled. The aims of this study were to investigate the role of the host microenvironment, and specifically fibroblasts, in ATLL pathogenesis and to propose a murine model for the lymphoma subtype. Here we present evidence that the oncogenic capacity of HTLV-1-immortalized C91/PL cells is enhanced when they are xenotransplanted together with human foreskin fibroblasts (HFF) in immunocompromised BALB/c Rag2-/-γc-/- mice. Moreover, cell lines derived from a developed lymphoma and their subsequent in vivo passages acquired the stable property to induce aggressive T cell lymphomas. In particular, one of these cell lines, C91/III cells, consistently induced aggressive lymphomas also in NOD/SCID/IL2Rγc KO (NSG) mice. To dissect the mechanisms linked to this enhanced tumorigenic ability, we quantified 45 soluble factors released by these cell lines and found that 21 of them, mainly pro-inflammatory cytokines and chemokines, were significantly increased in C91/III cells compared to the parental C91/PL cells. Moreover, many of the increased factors were also released by human fibroblasts and belonged to the known secretory pattern of ATLL cells. C91/PL cells co-cultured with HFF showed features reminiscent of those observed in C91/III cells, including a similar secretory pattern and a more aggressive behavior in vivo. On the whole, our data provide evidence that fibroblasts, one of the major stromal components, might enhance tumorigenesis of HTLV-1-infected and immortalized T cells, thus throwing light on the role of microenvironment contribution in ATLL pathogenesis. We also propose that the lymphoma induced in NSG mice by injection with C91/III cells represents a new murine preclinical ATLL model that could be adopted to test novel therapeutic interventions for the aggressive lymphoma subtype.

HTLV‑1‑associated genes as potential biomarkers for endometrial cancer

“…Thus, efforts have been made to prevent HTLV-1-associated carcinogenesis, and recently, a therapy targeting C-C motif chemokine receptor 4, which has been identified as an adult T-cell leukemia-specific marker associated with HTLV-1, has been clinically tested in Japan with promising results (15). Previous studies explored the mechanisms underlying HTLV-1-mediated tumorigenesis, including the promotion of cell proliferation and modulation of multiple host factors in liver cancer and lymphoma (16–18). HTLV-1 differs from other acute transforming retroviruses, and may not rapidly initiate carcinogenesis or alter the expression pattern of cellular proto-oncogenes (16).…”

Microbial Biofilms: Human T-cell Leukemia Virus Type 1 First in Line for Viral Biofilm but Far Behind Bacterial Biofilms

“…The contribution of the tumor microenvironment in ATL development is not yet completely unraveled. However, using a transgenic and humanized mouse model, Vicario et al showed that fibroblasts might enhance tumorigenesis of HTLV-1-infected and immortalized T cells, thus shedding light on the microenvironment contribution in ATL pathogenesis (Vicario et al, 2018). Although it is not denied that the direct or indirect ECM remodeling by viruses is involved in tissue infiltration and in the anti-tumor host's immune response, the role of viral biofilm, which is constituted of ECM components involved in cancer pathogenesis, has never been investigated.…”

Novel Immunotherapies for T Cell Lymphoma and Leukemia

“…In vitro interaction with epithelial and fibroblastic cell-lines was shown to induce apoptosis resistance in primary ATLL cells and ATLL cell lines(18), as well as HTLV1 latency(19). In ATLL models, fibroblasts acquire an activated pro-inflammatory phenotype enhancing tumorigenesis(20). Interestingly, MF and SS cells have the potential to inhibit normal T-cell proliferation and suppress dendritic cells maturation by secreting Th2-type cytokines (21).…”