Blockade of the Immune Checkpoint CD47 By TTI-621 Potentiates the Response to Anti-PD-L1 in Cutaneous T Cell Lymphoma

Cutaneous T cell lymphoma (CTCL) is an incurable and cosmetically disfiguring disease associated with microenvironmental signals. We investigated the effects of CD47 and PD-L1 immune checkpoint blockades, as a strategy for targeting both innate and adaptive immunity. CIBERSORT analysis identified the immune cell composition in the CTCL tumor microenvironment and the immune checkpoint expression profile for each immune cell gene cluster from CTCL lesions. We investigated the relationship between MYC and CD47 and PD-L1 expression and found that MYC shRNA knockdown and MYC functional suppression by TTI-621 (SIRPαFc) and anti-PD-L1 (durvalumab) in CTCL cell lines reduced the expression of CD47 and PD-L1 mRNA and protein as measured by qPCR and flow cytometry, respectively. In vitro, blockade of the CD47-SIRPα interaction with TTI-621 increased the phagocytic activity of macrophages against CTCL cells and enhanced CD8 T-cell-mediated killing in a mixed leucocyte reaction. Moreover, TTI-621 synergized with anti-PD-L1 in macrophages reprogram to M1-like phenotypes and inhibited CTCL cell growth. These effects were mediated by cell‒death-related pathways, including apoptosis, autophagy, and necroptosis. Collectively, our findings demonstrate that CD47 and PD-L1 are critical regulators of immune surveillance in CTCL and dual targeting of CD47 and PD-L1 will provide insight into tumor immunotherapy for CTCL.