Abstract 5196: CD47 Blockade potentiates immunotherapy of durvalumab against cutaneous T cell lymphoma
Authors: Han Zhen , Feng Mingye , Wu Xiwei , Su Chingyu , Yuan Yate-Ching , Qin Hanjun , Sanchez James F. , Zain Jasmine , Rosen Steven T. , Querfeld Christiane 
Published: June 2022

Immune checkpoint (IC) blockade for programmed cell death 1 (PD1) and PD-Ligand 1 (PD-L1) has shown promising and durable therapeutic outcomes in cutaneous T-cell lymphoma (CTCL), but resistance and/or relapses are common. While research focused on improving adaptive immune functions in CTCL, we investigated the role of 1) the “do not eat me signal” (CD47), and PD-L1, as a dual (innate and adaptive IC)-targeting strategy in CTCL. RNA sequencing and flow cytometric analysis showed that CTCL tumor cells and CTCL cell lines (MyLa, Hut78, HH, and H9 cells) overexpressed CD47 and PD-L1 compared with healthy control, and CD47 positively correlated with PD-L1 in CTCL patients. Overexpression of CD47 and PD-L1 was induced by high MYC expression in CTCL tumor cells lines. In addition, the signal-regulatory protein (SIRP)α receptor for CD47 and PD-L1 were significantly more abundant on macrophages, dendritic cells and natural killer cells in CTCL patients than healthy control by flow cytometric analysis. Furthermore, the RNA sequencing data indicated that the M2 macrophages, immature dendritic cells, and inhibitory receptors expressed natural killer cells in CTCL patients were higher than in healthy control. Notably, TTI-621 (SIRPαFc) treatment decreased M2 macrophage, immature dendritic cells, and inhibitory receptors expressed natural killer cells in CTCL patients at the end of the treatment, compared to baseline. In vitro, TTI-621 treatment increased the macrophage phagocytic activity compared to untreated control. Moreover, TTI-621 synergized with an anti-PD-L1 antibody (durvalumab) to reprogram M2-like TAMs, induced by MyLa supernatant, to M1-like phenotypes. The simultaneous blockade of both CD47 and PD-L1 inhibited growth of CTCL cell lines more potently than each single antibody alone or blank control in vitro. Enhanced CD8+ T cell mediated killing was detected using a chromium-release assay following dual blockade of in CTCL cell lines, suggesting anti-CD47 and anti-PD-L1 may synergistically facilitate elimination of CTCL tumor cells through specific pathways. RNA-sequencing analysis indicated that these effects were mediated by cell death related pathways such as apoptosis, autophagy, and necroptosis. Collectively, our findings demonstrated that CD47 and PD-L1 are critical regulators of innate and adaptive immune surveillance in CTCL and that dual targeting of CD47 and PD-L1 will provide insight into tumor immunotherapy to improve tumor control in CTCL.

Citation Format: Zhen Han, Mingye Feng, Xiwei Wu, Chingyu Su, Yate-Ching Yuan, Hanjun Qin, James F. Sanchez, Jasmine Zain, Steven T. Rosen, Christiane Querfeld. CD47 Blockade potentiates immunotherapy of durvalumab against cutaneous T cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5196.