Gang Zhou, PhD
Professor, Georgia Cancer Center, Department of Medicine, Medical College of Georgia
Professor, Department of Biochemistry and Molecular Biology
Professor, The Graduate School, Augusta University
The Zhou Laboratory studies how chemotherapeutic agents modulate the tumor microenvironment (TME) and how their immunomodulatory effects can be exploited to facilitate cancer immunotherapy. The research focus of the lab is to understand how intrinsic and extrinsic factors shape the functional status of tumor-reactive CD4+ T cells in the post-chemotherapy setting. Studies from Dr. Zhou’s group have revealed critical mechanisms governing the generation of polyfunctional CD4+ T cells, chemotherapy-induced immunosuppressive myeloid cells, and T cell-driven alteration of tumor metabolism. These findings may aid in the development of more efficacious cancer immunotherapy.
Using a mouse model of B-cell lymphoma, we reported that tumor antigen-specific CD4+ T cells undergo aberrant differentiation in the tumor setting, acquiring a dysfunctional phenotype and/or immunosuppressive activities. Certain widely-used chemotherapeutic agents, with cyclophosphamide as an example, can reprogram the tumor microenvironment from tolerogenic to immunogenic, thereby promoting the effector differentiation and clonally expansion of tumor-specific CD4+ T cells. These polyfunctional CD4+ effector cells in turn act as the “gatekeeper” of the host antitumor immunity, and their functional status critically determines the outcome between eradication and regrowth of the residual tumors. Our studies include identifying and characterizing novel CD4+ T cell-potentiating chemotherapeutic agents, elucidating the mechanisms by which CD4+ effector cells activate other tumor-reactive immune cells, revealing the transcriptomic and epigenetic landscapes dictating CD4+ T cell polyfunctionality. Findings from these studies will provide mechanistic basis for the design of more effective chemo-immunotherapy strategies that capitalize on the therapeutic potential of CD4+ T cells.
Tumor recurrence remains a major problem for patients with cancer. With the recent advances in immune-based therapeutic strategies, there is growing interest to synergistically combine immunotherapy with conventional chemotherapy to achieve durable antitumor effects. In some cases, chemotherapy-induced myeloid suppressor cells represent a critical obstacle to this goal. We recently reported that certain standard-of-care chemotherapeutic agents, including cyclophosphamide, melphalan and doxorubicin, can induce the expansion of immunosuppressive monocytic myeloid cells. We showed that selective depletion of chemotherapy-induced inflammatory monocytes following chemo-immunotherapy significantly improved long-term survival, providing evidence that therapy-induced monocytes contribute to tumor immune evasion and relapse. Our results suggest that the net impact of chemotherapy on tumor immunity is a dynamic balancing act between its two opposing immunomodulatory effects. Thus, targeting therapy-induced myeloid suppressor cells will allow robust response to immunotherapies in the post-chemotherapy window, thereby tilting the balance toward a durable therapeutic outcome.
Non-steroidal anti-inflammatory drugs (NSAIDs) such as sulindac can exert immunopotentiating effect by inhibiting the activities of cyclooxygenases (COX). However, long-term inhibition of COX can cause severe toxicities in some vital organs. This project will develop novel non-COXinhibitory sulindac derivatives and employ them as immunomodulators to augment the efficacy of cancer immunotherapies by targeting specific phosphodiesterase (PDE) instead of COX.
Zhi-Chun Ding, Huidong Shi, Kateryna Fesenkova, Nada Aboelella, Eun-Jeong Park, Zhuoqi Liu, Lirong Pei, Jiaqi Li, Richard A. McIndoe, Gary A. Piazza, Bruce R. Blazar, David H. Munn and Gang Zhou. Persistent STAT5 activation in CD4+ T cells induces transcriptional and epigenetic remodeling to drive polyfunctionality and antitumor immunity. Science Immunology. 30 Oct 2020:Vol. 5, Issue 52, eaba5962. DOI: 10.1126/sciimmunol.aba5962.
Antonio B. Ward, Adam B. Keeton, Xi Chen, Tyler E. Mattox, Alex B. Coley, Yulia Y. Maxuitenko, Donald J. Buchsbaum, Troy D. Randall, Gang Zhou, Gary A. Piazza. Enhancing anticancer activity of checkpoint immunotherapy by targeting RAS. MedComm. 25 June, 2020.
Tsadik Habtetsion, Zhi-Chun Ding, Wenhu Pi, Tao Li, Chunwan Lu, Tingting Chen, Caixia Xi, Helena Spartz, Kebin Liu, Zhonglin Hao, Nahid Mivechi, Yuqing Huo, Bruce R. Blazar, David H. Munn and Gang Zhou. (2018) Alteration of Tumor Metabolism by CD4+ T Cells Leads to TNF-a-Dependent Intensification ofOxidative Stress and Tumor Cell Death. Cell Metabolism. 2018. 7;28(2):228-242.
Kuczma MP, Ding ZC, Li T, Habtetsion T, Chen T, Hao Z, Bryan L, Singh N, Kochenderfer JN, Zhou G. The impact of antibiotic usage on the efficacy of chemoimmunotherapy is contingent on the source of tumor-reactive T cells. Oncotarget. 2017; 8(67):111931-111942.
Ding ZC, Habtetsion T, Cao Y, Li T, Liu C, Kuczma M, Chen T, Hao Z, Bryan L, Munn DH, Zhou G. Adjuvant IL-7 potentiates adoptive T cell therapy by amplifying and sustaining polyfunctional antitumor CD4+ T cells. Scientific Reports. 2017 Sep 22;7(1):12168. doi: 10.1038/s41598-017-12488-z.
Ding ZC, Liu C, Cao Y, Habtetsion T, Kuczma M, Pi W, Kong H, Cacan E, Greer SF, Cui Y, Blazar BR, Munn DH and Gang Zhou. IL-7 signalling imparts polyfunctionality and stemness potential to CD4+ T cells. OncoImmunology. 2016; 5(6):e1171445.
Lu X, Ding ZC, Cao Y, Liu C, Habtetsion T, Yu M, Lemos H, Salman H, Xu H, Mellor AL, and Gang Zhou. Alkylating agent melphalan augments the efficacy of adoptive immunotherapy using tumor-specific CD4+ T cells. J Immunol. 2015; 194(4):2011-21.
Zhi-Chun Ding, Xiaoyun Lu, Miao Yu, Henrique Lemos, Lei Huang, Phillip Chandler, Kebin Liu, Matthew Walters, Antoni Krasinski, Matthias Mack, Bruce R. Blazar, Andrew L. Mellor, David H. Munn, and Gang Zhou. Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses via the PD1/PDL1 axis. Cancer Research. 2014; 74(13); 3441-53.
Zhou G, Levitsky HI. (2012) Towards curative cancer immunotherapy: overcoming post-therapy tumor escape. Clinical and Developmental Immunology. 2012:124187. Epub 2012 May 31. PMID:22778760.
Ding, ZC, Huang L, Yagita H, Blazar BR, Mellor AL, Munn DH, Zhou G. (2012) Polyfunctional CD4+ T cells are essential for eradicating advanced B-cell lymphoma after chemotherapy. Blood. 120(11):2229-39.
Zhi-Chun Ding and G. Zhou. (2012) Cytotoxic chemotherapy and CD4+ effector T cells: an emerging alliance for durable antitumor effects. Clinical and Developmental Immunology. 2012:890178. Epub Feb 6. PMID:22400040.
Ding, ZC, Blazar BR, Mellor AL, Munn DH, ZhouG. (2010) Chemotherapy rescues tumor-driven aberrant CD4+ T-cell differentiation and restores an activated polyfunctional helper phenotype. Blood. 115:2397-406.
Dr. Zhi-Chun Ding