Th155 - Role of Cell Adhesion Receptors in Recruitment and Functional Plasticity of Tumor Associated Macrophages

Nibedita Dalpati – Biosciences and Bioengineering – Indian Institite of Technology Roorkee; Shiba Prasad Dash – Biosciences and Bioengineering – Indian Institute of Technology Roorkee; Puneet Kumar – Biosciences and Bioengineering – Indian Institute of Technology Roorkee; Shubham Rai – Indian Institute of Technology Roorkee; Divya Singh – Biosciences and Bioengineering – Indian Institute of Technology Roorkee

Abstract Text: Tumor-associated macrophages (TAMs) drive the protumorigenic responses and facilitate tumor progression via matrix remodeling, angiogenesis, and immunosuppression. Leukocyte migration and their interaction with extracellular matrices via cell surface integrins are essential in the immunological responses. However, little is known about the expression dynamics of integrin cell adhesion receptors and their correlation with functional plasticity of macrophages in tumor microenvironments. Our present data show that in a 4T1 mouse mammary tumor model, at day 10, when palpable tumors are detected, CD11b+Ly6Chi monocytes in both bone marrow and blood showed higher expression of integrin α5β1 along with CCR2 and CXCR4. At day 15, while higher expression of integrin α5β1 was found on tumor-infiltrating monocytes (Ly6ChiMHCIIlow) and M1-TAMs (F4/80+Ly6ClowMHCIIhi), higher levels of integrin αvβ3 were observed on the M2-TAMs (F4/80+Ly6ClowMHCIIlow). Additionally, upregulated expression of integrin α5β1 and αvβ3 was shown in CD206hi and MERTKhi cells in different TAM subsets (M1 and M2) in tumors and lungs at day 30 post induction. Further analysis suggested that CD11b+Ly6G-F4/80+α5+ TAMs displayed increased levels of inflammatory cytokines and CD11b+Ly6G-F4/80+αv+ TAMs displayed a pro-tumorigenic phenotype with higher il-10, arg1, and tgf-β transcripts. Blocking of integrin α5 and αv during macrophage differentiation reduced expression of M2 marker (CD206 and CD163) and VEGF and arg1transcripts. Bioinformatics analysis revealed the involvement of ptk2 (FAK) and SRC protein kinases in the functional polarization of TAMs in breast tumors. In conclusion, our data shows that signaling via integrin play an essential role in the recruitment, polarization, and tumor environment mediated reprograming of TAMs.