Ying Zhang
Email：ying.zhang@pku.edu.cn
Research Area:
There is a pressing need to develop novel therapeutics that could turn T cell-excluded “cold” tumors into T cell-inflamed “hot” tumors to advance the efficacy of cancer immunotherapy. Cancer cells undergo distinct forms of programmed cell death (PCD) following stress, killer lymphocyte attack and drugs, which can greatly affect immune activation and sensitivity to treatment. Apoptosis, a major form of cancer cell PCD, tends to be anti-inflammatory and promote immune tolerance. Pyroptosis, by contrast, is a more rapid, lytic, and highly inflammatory form of PCD. Both pyroptosis and necroptosis, another type of inflammatory cell death, are implicated as forms of immunogenic cell death (ICD) that could drive robust antitumor immunity. An overarching hypothesis of our research program is that inducing inflammatory cell death in the tumor would serve as a powerful approach to awaken antitumor immunity and immunotherapy responsiveness.
Pyroptosis is mediated by cleavage of gasdermin (GSDM) proteins that produce N-terminal fragments, which form pores in the plasma membrane that permeablize the cells to induce cytosolic molecules release and cell burst. All GSDM family members, including GSDMA-E as well as DFNB59 possess pore-forming activity. Our previous work shows that during killer lymphocyte attack, granzyme B (GzmB) released from tumor-infiltrating lymphocytes (TILs) could directly cleave GSDME to induce GSDME-mediated cancer cell pyroptosis, which potently inhibited tumor growth and improved antitumor immunity. This work illustrates GSDME’s function as a tumor suppressor gene and reveals its activation mechanism in the tumor, demonstrating the power of pyroptosis in promoting antitumor immune responses. However, little is known about how pyroptosis and other forms of inflammatory cell death modulate antitumor immunity. How genes involved in the process of inflammatory cell death are regulated and their activation mechanism also remain largely unknown. Moreover, functions of GSDM beyond its involvement in pyroptosis remain a mystery. To address these questions, our laboratory will carry out studies in the following areas:
I. Determine how pyroptosis and other forms of inflammatory cell death affects tumor immune signature to inhibit tumor growth.
II. Explore mechanisms to promote inflammatory cell death and innate immune signaling as potent cancer immunotherapy.
III. Explore novel functions of GSDM proteins in the tumor.
Selected Publications:
Zhang Y, Xie X, Yeganeh PN, Lee DJ, Valle-Garcia D, Meza-Sosa KF, Junqueira C, Su J, Luo H, Hide W, Lieberman J. Immunotherapy for breast cancer using EpCAM aptamer tumor-targeted gene knockdown. Proc Natl Acad Sci USA. 2021 March; 118(9): e2022830118.
Zhang Z, Zhang Y, Judy Lieberman. Lighting a Fire: Can We Harness Pyroptosis to Ignite Antitumor Immunity? Cancer Immunology Research. 2021; 9 (1) 2-7.
Zhang Z*, Zhang Y*, Xia S, Kong Q, Li S, Liu X, Junqueira C, Meza-Sosa KF, Mok TMY, Ansara J, Sengupta S, Yao Y, Wu H, Lieberman J. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature. 2020 Mar;579(7799):415-420 *Co-first Author with Equal Contribution.
Research Highlighted by:
Nature Reviews Immunology. 2020 May;20(5):274-275. doi: 10.1038/s41577-020-0297-2.
Nature Reviews Drug Discovery. 2020 May;19(5):309. doi: 10.1038/d41573-020-00062-8.
Science. 2020 May 29;368(6494):943-944. doi: 10.1126/science.abc2502.
Science Signaling. 2020 March; 13(624). doi: 10,1038/d41573-020-00062-8.
Signal Transduction Targeted Therapy. 2020 May 13;5(1):69. doi: 10.1038/s41392-020-0180-4.
Hu JJ, Liu X, Xia S, Zhang Z, Zhang Y, Zhao J, Ruan J, Luo X, Lou X, Bai Y, Wang J, Hollingsworth LR, Magupalli VG, Zhao L, Luo HR, Kim J, Lieberman J, Wu H. FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nature Immunology. 2020 Jul;21(7):736-745.
Zhang Y, Kurupati R, Liu L Zhou XY, Zhang G, Hudaihed A, Filisio F, Giles-Davies W, Xu W, Karakousis GC, Schuchter LM, Xu W, Amaravadi R, Xiao M, Sadek N, Krepler C, Herlyn M, Freeman GJ, Rabinowitz J, Ertl HC. Enhancing CD8+ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell. 2017 Sept; 32(3):377-391.e9.
Research Highlighted by:
Nature Reviews Cancer. 2017 Nov;17(11):635. doi:10.1038/nrc.2017.94.
Cancer Cell. 2017 Sep; 32(3):280-281. doi: 10.1016/j.cell.2017.08.013.
Cancer Discovery. 2017 Nov; 7(11):1213. doi:10.1158/2159-8290.CD-RW2017-182.
Zhang Y, Ertl HC. Aging: T cell metabolism within tumors. Aging. 2016 Jun; 8(6):1163-4.
Zhang Y, Ertl HC. Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors. Oncotarget. 2016; 7(17): 23282-23299.
Zhang Y, Ertl HC. Starved and asphyxiated: how can CD8+T cells within a tumor microenvironment prevent tumor progression. Frontiers in Immunology. 2016;7(32).
Zhang Y, Ertl HC. The effect of adjuvanting cancer vaccines with herpes simplex virus glycoprotein D on Melanoma-Driven CD8+T cell exhaustion. Journal of Immunology. 2014; 193(4): 1836-1846.
Meza-Sosa KF, Miao R, Navarro F, Zhang Z, Zhang Y, Hu JJ, Hartford C, Li X, Pedraza-Alva G, Pérez-Martínez L, Lal A, Wu H, Lieberman J. SPARCLE, a p53-induced lncRNA, controls apoptosis after genotoxic stress by promoting PARP-1 cleavage. Molecular Cell. 2022, 82(4): 785-802.
Vora SM, Fontana P, Mao T, Leger V, Zhang Y, Fu TM, Lieberman J, Gehrke L, Shi M, Wang LF, Iwasaki A, Wu H. Targeting Stem-loop 1 of the SARS-CoV-2 5’UTR to suppress viral translation and Nsp1 evasion. Proc Natl Acad Sci USA 2022, 119(9): e2117198119.