Bone Marrow Tumor Microenvironment of Obese Hodgkin Lymphoma Patients: implications of insulin axis

Abstract

Abstract Background Excessive adiposity, or obesity, has been associated with cancer promotion, including an increased risk for developing Hodgkin Lymphoma (HL). However, the association between obesity and survival in HL can be somewhat paradoxical and may indeed influence prognosis. Examining the bone marrow (BM) cytokine profile in HL patients could provide insights into the mechanisms underlying the altered association between excess adiposity and HL. The BM is an important site for hematopoiesis and can be influenced by various factors, including disease processes and systemic metabolic changes associated with obesity. Methods From our cohort, we analyzed interstitial marrow fluid (IMF) from BM aspirates of 16 HL patients at diagnosis and 11 control subjects. Participants were then matched by sex, age, and Body mass index (BMI) for inclusion in our discovery protein array analysis (n = 8 HL and n = 8 donors). We validated our findings in the total sample by measuring adipokine-related molecules using ELISA. Adiposity was measured through abdominal circumference measurement and BMI. Gene expression analysis was conducted through RT-qPCR. Activated signaling pathways were analyzed using HL cell line (L428 cells). Statistical analyses were performed using SPSS and GraphPad. Results The IMF of HL patients presented downregulation of interleukins (IL-1α/β, IL-6sR, IL-12), chemokines (CCL2, CCL3, CCL16), IGF-axis mediators (IGFBP-1, IGFBP-2, IGFBP-3, IGF-1sR), sTNFRII, TGFβ1, leptin, osteoprotegerin (OPG), and Fas compared to healthy donors and after controlling for adiposity status. Interestingly, HL overweight/obese subjects showed up-regulation of OPG and lymphotactin in IMF. The results were confirmed by quantification of cytokines, where we observed lower levels of insulin growth factor binding protein IGFBP-3 and higher levels of OPG levels in HL patients. The high-molecular weight (HMW) and total of adiponectin levels were high in HL BM. We further demonstrate that LEPR, TGFβ1, and IGFBP3 transcripts were upregulated in fractionated BMAd from HL compared to controls, while IFG2R was upregulated in SC. Finally, we observed a possible modulation of L428 cells through IGFBP-3 in an IGF-1-dependent manner, which could be reflected in the BM TME of HL disease. Conclusions Our data supports a role for the insulin axis in the BM microenvironment of obese HL patients, particularly through the regulation of insulin ligand-binding proteins.