SIRPα expression delineates subsets of intratumoral monocyte/macrophages with different functional and prognostic impact in follicular lymphoma.

Signal regulatory protein-α (SIRPα) is a key member of the "do-not-eat-me" signaling pathway, but its biological role and clinical relevance in B-cell NHL is relatively unknown. Using biopsy specimens from follicular lymphoma (FL), we identified three subsets (CD14 ⁺ SIRPα ^hi , CD14 ^- SIRPα ^low , and CD14 ^- SIRPα ^neg ) of monocyte/macrophages (Mo/MΦ) based on CD14 and SIRPα expression. CD14 ⁺ SIRPα ^hi cells expressed common Mo/MΦ markers; exhibited characteristic differentiation, migration, and phagocytosis; and suppressed T-cell function. CD14 ^- SIRPα ^low cells expressed fewer typical Mo/MΦ markers; migrated less and phagocytosed tumor cells less efficiently; and stimulated rather than suppressed T-cell function. Interestingly, the CD14 ^- SIRPα ^neg subset expressed distinct Mo/MΦ markers compared to the other two subsets; had limited ability to migrate and phagocytose; but stimulated T-cell function. When using SIRPα-Fc to block the interaction between SIRPα and CD47, alone or in combination with rituximab, phagocytosis of tumor cells was differentially increased in the three Mo/MΦ subsets. Clinically, increased numbers of CD14 ⁺ SIRPα ^hi cells were associated with an inferior survival in FL. In contrast, increased numbers of the CD14 ^- SIRPα ^low subset appeared to correlate with a better survival. Taken together, our results show that SIRPα expression delineates unique subsets of intratumoral Mo/MΦs with differing prognostic importance.