Session: 621. Lymphomas: Translational—Molecular and Genetic: Poster II
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Translational Research
1Division of Dermatology, City of Hope, Duarte, CA; 2Beckman Research Institute, City of Hope, Duarte, CA; 3Department of Molecular and Cellular Biology, City of Hope, Duarte, CA; 4Integrative Genomics Core, City of Hope, Duarte, CA; 5Department of Computational Quantitative Medicine, City of Hope, Duarte, CA; 6Translational Bioinformatics, Center for informatics, City of Hope, Duarte, CA; 7Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA; 8Cutaneous Lymphoma Program, Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, PA; 9Department of Immuno-Oncology, City of Hope, Duarte, CA; 10Department of Pathology, City of Hope, Duarte, CA.
Background: Blockade of PD1/PD-L1 (NCT03011814) and CD47/SIRPα (NCT02890368) have shown promising and durable therapeutic outcomes in cutaneous T-cell lymphoma (CTCL), but resistance and/or relapses are seen in a subset of patients. To improve outcomes of immunotherapy regimens for CTCL patients, we investigated the effects of dual CD47 and PD-L1 blockade as a strategy for targeting both the innate and adaptive immune system.
Methods: We performed RNA sequencing, gene expression deconvolution (CIBERSORT) and flow cytometry analysis to assess the immune cell composition, and CD47, SIPRα and PD-L1 expression in 45 CTCL patient samples and CTCL cell lines. CTCL specimens at baseline and during treatment with anti-CD47/SIRPα (TTI621) and anti-PD-L1 (durvalumab) were used to analyze immune cell gene expression. We performed functional assays utilizing our macrophage and CTCL cell line culture systems to assess macrophage polarization, phagocytic activity of macrophages against CTCL cells, T cell-mediated cytotoxicity using a chromium release assay, and CTCL cell line proliferation before and after CD47/SIRPα (TTI-621) and anti-PD-L1 antibody (durvalumab) treatment.
Results: Our data showed that CTCL cells and CTCL cell lines overexpress CD47 and PD-L1 compared with healthy control cells, and overexpression of CD47 and PD-L1 was associated with high MYC expression in CTCL cell lines. CIBERSORT analysis of CTCL samples compared to healthy control indicated that the fraction of M2 tumor-associated macrophages (TAMs) was increased, while M0/1 were significantly lower. Our NanoString data showed decreased M2 genes, immature DC-related genes, and the NK cell inhibitory receptor related genes, but up-regulation of M1 genes and the NK cell stimulatory receptors associated genes for CTCL patients after treatment with TTI-621 compared to baseline. In vitro, treatment with TTI-621 increased the phagocytic activity of macrophages against CTCL cells and enhanced CD8+ T-cell-mediated killing. Moreover, TTI-621 synergized with anti-PD-L1 (durvalumab) to reprogram M2-like tumor-associated macrophages to M1-like phenotypes by inhibiting MYC expression. Simultaneous exposure to TTI-621 and anti-PD-L1 inhibited growth of CTCL cell lines more potently than either antibody alone. RNA sequencing analysis indicated these effects were mediated by cell‒death-related pathways, such as apoptosis, autophagy, and necroptosis.
Conclusions: Collectively, our findings demonstrate that CD47 and PD-L1 are critical regulators of the immune microenvironment in CTCL and that dual targeting of CD47 and PD-L1 may potentiate anti-tumor responses in CTCL.
Disclosures: Zain: Secura Bio: Consultancy, Research Funding; Daichi Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Myeloid: Consultancy, Research Funding; CRSPR: Research Funding; Seattle Genetics: Research Funding, Speakers Bureau; 3M: Current holder of stock options in a privately-held company; Affirmed: Research Funding; Kiyowa Kirin: Speakers Bureau. Rosen: January Therapeutics: Current holder of stock options in a privately-held company. Feng: Innovent Biologics: Consultancy. Querfeld: Trillium: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Investigator; Bristol Meyer Squibb: Other: Clinical Investigator; Celgene: Research Funding; Helsinn: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Mallinckrodt: Membership on an entity's Board of Directors or advisory committees; Bioniz: Membership on an entity's Board of Directors or advisory committees.
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