7095 Background: While sex-specific disease incidence, genomic profiles, and survival outcomes are widely recognized in hematologic malignancies, the biological mechanisms and tumor microenvironment (TME) factors driving these sex-based disparities remain largely undefined, particularly at the level of the TME, which plays a key role in immune surveillance, therapeutic response, and disease progression. This meta-analysis investigates whether significant differences exist in the abundance of various cell types between males and females within lymphoid and myeloid leukemias, plasma cell tumors, mature B-cell lymphomas, and acute lymphoblastic leukemia. Characterizing these variations is essential for developing tailored therapeutic strategies that optimize clinical outcomes for both sexes. Methods: Computational meta-analysis was performed on the TCGA National Database, using xCell enrichment scores across transcriptomic samples from hematopoietic and reticuloendothelial system tumors, comparing males (n= 3,829) and females (n= 2,995). Mann-Whitney U testing with Bonferroni correction identified cell populations with differential enrichment (padj0.05). Results: Of the 64 cell types screened, 12 exhibited a significant difference in abundance between males and females. Nine of these were female-enriched populations (padj <0.01). These included erythrocytes (Mean Difference Male-Female: -0.5192), neutrophils (-0.4343), eosinophils (-0.4147), GMP (-0.1345), platelets (-0.1097), common myeloid progenitors (CMP) (-0.0917), mast cells (-0.0640), MPP (-0.0556), and megakaryocytes (-0.0131) indicating higher relative enrichment in females. Conversely, the male-enriched populations (padj <0.02) consisted of DC (0.2210), Th2 cells (0.0761), and Th1 cells (0.0634). Conclusions: This study demonstrates sex-based differences in TME cellular abundance in hematopoietic and reticuloendothelial tumors. Females exhibited a higher presence of early-stage progenitor populations, such as MPP and CMP, and innate immune cells, including neutrophils and eosinophils, potentially due to hormonal influences, differences in myelopoiesis, or sex-linked immune polarization. In contrast, males had a higher presence of DC and Th cells. Among all cell types analyzed, erythrocytes exhibited the greatest magnitude of difference in abundance between sexes, showing potential distinctions in metabolic and oxygenation profiles. These findings highlight biologically meaningful sex specific variations in the TME, underscoring the need for further mechanistic studies linking sex-specific TME compositions to therapeutic responses and incorporating biological sex as a critical variable in immunotherapy trial design.
Vaz et al. (Thu,) studied this question.