Supplementary Methods; Figures S1 - S22; Tables S2, S6, S9 - S12 from CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade
Year: 2023
Type: supplementary-materials
Abstract: Supplementary title page. Figure S1: CD38 on anti-PD-L1 resistant tumor cells is up-regulated, which is associated with tumor progression. Figure S2: anti-PD-L1 resistant tumors demonstrate the distinct mRNA and protein profiling for immune signature, reflecting the upregulation of CD38. Figure S3: PD-1/PD-L1 blockade results in CD38 up-regulation and acquired resistance in KP-derived lung and melanoma transplantation tumors. Figure S4: Tumor-associated PD-L1 promotes tumor growth but PD-L1 knockout cancer cells still form tumors. Figure S5: PD-L1 knockout effect on tumor growth is CD8 T cell-dependent. Figure S6: CD38 up-regulation after anti-PD-L1 treatment is associated with all-trans retinoic acid signaling. Figure S7: IFN-b, which is enriched in anti-PD-L1 treated tumors, up-regulates CD38 expression on multiple cancer cell lines. Figure S8: IRF1, which links ATRA and IFN-b, is upregulated after anti-PD-L1 treatment. Figure S9: IFN-g, TNF-a, IL-2, and IL-1b don''t regulate CD38 expression on lung cancer cells. Figure S10: The anti-PD-L1 resistant tumors demonstrate an immune suppressive microenvironment. Figure S11: CD38 substantially changes in vivo tumor formation of PD-L1KO cancer cells, but does not change in vitro cell growth rate and cell cycle. Figure S12: The elimination of PD-L1KOCD38negative cancer cells is CD8+ T cell dependent. Figure S13: CD38 on tumor cells inhibits CD8+ T cell function and protects tumor cells from CD8+ T cell killing. Figure S14: CD38-mediated CD8+TIL dysfunction is not affected by tumor growth rate/tumor size. Figure S15: CD38 expression in cancer cell lines and patient tissues, which is associated with the differentiated immune features. Figure S16: CD38 or PD-L1 expression is not correlated with overall survival in early-stage lung cancer. Figure S17: Pre-treatment levels of CD38 and PD-L1 expression in NSCLC patients who received anti-PD-1/PD-L1 therapy, as divided by clinical outcome. Figure S18: The effect of cancer immunotherapy by anti-CD38 is CD8 T cell dependent. Figure S19: Combined inhibitors of CD38 and PD-L1 inhibits tumor growth and metastases. Figure S20: The co-inhibition of PD-L1 and CD38 leads to a favorable antitumor immune microenvironment. Figure S21: Sequential treatment of anti-PD-L1 and anti-CD38 results in enhanced immune response in tumor microenvironment. Figure S22: anti-mouse CD38 antibody (NIMR-5) does not directly kill tumor cells through ADCC and CDC, but causes CD38 internalization. Table S2: Tumor immune markers with the greatest differential transcriptional levels after anti-PD-L1 treatment. Table S6: The most changed immune-related genes after anti-PD-L1 treatment. Table S9:The correlation between CD38 and suppressive immune markers in LUAD dataset. Table S10: The correlation between CD38 and suppressive immune markers in LUSC dataset. Table S11: The available NSCLC patients with CD38 and PD-L1 tumor cell IHC staining and responses to anti-PD-1 therapy. Table S12: The co-inhibition effect of PD-L1 and CD38 on tumor growth and metastasis. Supplementary Material and Methods: Reagents, Cells and Mice, CRISPR/Cas9 Editing, Antibody-mediated Cell Depletion, CD8+ T Cell Adoptive Transfer, mRNA Profiling of Murine Tumors, Flow Cytometry, Nanostring Analysis, qRT-PCR and Western Blotting, Liquid Chromatography-Mass Spectrometry (LC-MS) Analysis, Histologic Analysis, ELISA and RPPA, ADCC/CDC and Internalization Assays, Human Samples, Statistics. Supplementary references
Authors: Limo Chen, Lixia Diao, Yongbin Yang, Xiaohui Yi, B. Leticia Rodriguez, Yanli Li, Pamela A. Villalobos, Tina Cascone, Xi Liu, Lin Tan, Philip L. Lorenzi, Anfei Huang, Qiang Zhao, Di Peng, Jared J. Fradette, David H. Peng, Christin Ungewiss, Jonathon Roybal, Pan Tong, Junna Oba, Ferdinandos Skoulidis, Weiyi Peng, Brett W. Carter, Carl M. Gay, Youhong Fan, Caleb A. Class, Jingfen Zhu, Jaime Rodriguez-Canales, Masanori Kawakami, Lauren Averett Byers, Scott E. Woodman, Vassiliki A. Papadimitrakopoulou, Ethan Dmitrovsky, Jing Wang, Stephen E. Ullrich, Ignacio I. Wistuba, John V. Heymach, F. Xiao-Feng Qin, Don L. Gibbons
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4362539185