Abstract 3123: Peripheral T cell lymphoma-associated fibroblasts promote tumor growth in an in vivo model

Abstract

Abstract Peripheral T-cell lymphomas (PTCLs) represent a rare and heterogeneous group of aggressive non-Hodgkin's lymphomas comprising different entities. Anthracycline-based regimens (usually CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone) followed by stem cell transplantation are considered the standard of care in the front-line setting. However, long-term disease control can be achieved only in 30-40% of young patients. Increasing evidences highlight the role of tumor microenvironment in sustaining tumor progression and aggressiveness. Among microenvironment components, a central role is played by cancer associated fibroblast (CAFs). Recent studies demonstrated that this is applicable not only to solid tumors but also to haematological malignancies. Here, we report for the first time the isolation and characterization of PTCL-CAFs and their role in promoting cell proliferation. We kept in culture a skin biopsy of a cutaneous localization of a peripheral T cell lymphoma. Fibroblast-like cells grown out from the biopsy were isolated, cultivated for few passages and then characterized. Flow cytometric analyses revealed that the cell population entirely expressed cell-surface antigens specific for fibroblasts, such as CD140b and CD90, while they did not express CD45 and CD31, thus excluding hematopoietic or endothelial origin. Biochemical analyses confirmed that all cells were positive for vimentin, while αSMA expression highlighted the activated status of the cells isolated. We then assessed the in vitro effect of CAFs on PTCL cell growth by co-colture experiments. For this purpose, we coltured for 8 days the PTCL cell line OCI-Ly12 in fresh medium or in medium previously conditioned by CAFs or normal skin fibroblasts (NFs). PTCL cell growth was not affected by co-colture either with CAFs or with NFs. Moreover, the presence of conditioned medium did not alter the response of OCI-Ly12 cells to CHOP treatments. We then assessed the in vivo effect of PTCL-CAFs. We subcutaneously injected CAFs alone, OCI-Ly12 cells alone and OCI-Ly12 together with CAFs (ratio 1:1) in NOD/SCID mice and monitored tumor growth for 20 days. In contrast to the effect observed in vitro, co-injection of CAFs with cancer cells substantially promoted tumor growth (tumor volume OCI-Ly12 0,87±0,47 cm3; OCI-Ly12+CAFs 2,30±0,26 cm3). As expected, CAFs alone did not develop a measurable mass. Subsequent immunohistochemical staining with CD31 revealed the presence of more vascular structures in tumors originated by OCI-Ly12+CAFs co-injection than by OCI-Ly12 alone, suggesting that CAFs presence sustains tumor growth by promoting angiogenesis. In summary, we show that PTCL-derived CAFs promote cancer cell growth in vivo, while leaving unaffected cell growth in vitro and the response to chemotherapy. This is the first evidence of the role played by the microenvironment in promoting malignant cell proliferation in PTCLs. Citation Format: Martina Magni, Sara Rizzitano, Alessio Pellegrinelli, Paolo Corradini, Cristiana Carniti. Peripheral T cell lymphoma-associated fibroblasts promote tumor growth in an in vivo model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3123.