Clinical Fellow The University of Texas MD Anderson Cancer Center Houston, Texas, United States
Disclosure(s):
Anthos Christofides, MD, PhD: No financial relationships to disclose
Introduction/Rationale: Myeloid cells within the tumor microenvironment (TME) critically regulate cancer progression. Integrins orchestrate essential myeloid functions, including adhesion, migration, phagocytosis and antigen presentation. Rap1-interacting molecule (RIAM) is an indispensable component of integrin activation machinery. The role of RIAM in tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) is unknown.
Methods: To investigate this, we generated mice with myeloid-specific RIAM deletion (RIAM fl/fl LysM-Cre ) and implanted MC17-51 fibrosarcoma or B16-F10 melanoma.
Results: Compared to WT controls, RIAM fl/fl LysM-Cre mice developed significantly larger tumors indicating that RIAM expression in myeloid cells restrains tumor progression. Flow cytometry and RNA sequencing revealed that RIAM-deficient TAMs were skewed toward an M2-like phenotype, with upregulation of CD204, CD206, and CD163, and downregulation of CD86, CD88, and MHC-II. Transcriptomic pathway analysis showed enrichment of IL-4/IL-13 signaling and suppression of NF-κB–mediated inflammatory programs, consistent with impaired pro-inflammatory function. In contrast, RIAM-deficient splenic MDSCs had attenuated immunosuppressive capacity. Thus, despite impaired MDSC activity, RIAM deletion in the myeloid compartment accelerates tumor growth by reprogramming TAMs toward a tumor-promoting state.
Conclusion: These findings identify RIAM and integrin signaling as novel therapeutic targets for reversing TAM-mediated tumor progression.
