Cancer Immunology, Inflammation & Tolerance


The Zhou laboratory studies how chemotherapeutic agents modulate the tumor microenvironment and how their immunomodulating effects can be exploited to facilitate cancer immunotherapy. The major  focus is delineating the gate-keeper role of tumor-specific CD4+ T cells in the post-chemotherapy setting. 

The synergy of chemotherapy and CD4+ effector T cells in mediating potent antitumor effects

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, determining the molecules/pathways involved in sustaining or attenuating the function and survival of CD4+ effector cells. 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 to cure cancer.

Chemotherapy-induced inflammatory myeloid cells and tumor relapse

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.

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.

Zhou G, Ding ZC, Fu J, Levitsky HI. (2011) Presentation of Acquired Peptide-MHC Class II Ligands by CD4+ Regulatory T Cells or Helper Cells Differentially Regulates Antigen-Specific CD4+ T Cell Response. J Immunol. 186(4):2148-55.

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, 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.

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.

Marabelle A, Kohrt H, Sagiv-Barfi I, Ajami B, Axtell RC, Zhou G, Rajapaksa R, Green MR, Torchia J, Brody J, Luong R, Rosenblum MD, Steinman L, Levitsky HI, Tse V, Levy R. (2013) Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. Journal of Clinical Investigation.123(6):2447–63.

Xu Y, An X, Guo X, Habtetsion T, Wang Y, Xu X, Li Q, Li H, Zhang C, Caldwell RB, Fulton DJ, Su Y, Hoda N, Zhou G, Wu C, Huo Y. (2014) Endothelial 6-phosphofructo-2-kinase (PFKFB3) plays a critical role in angiogenesis. The Journal of Arteriosclerosis, Thrombosis, and Vascular Biology.34(6):1231-9.

Ding ZC, Lu X, Yu M, Lemos H, Huang L, Chandler P, Liu K, Walters M, Krasinski A, Mack M, Blazar BR, Mellor AL, Munn DH, Zhou G. (2014) Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses via the PD1/PDL1 axis. Cancer Research.74(13):3441-53.

Ding ZC, Munn DH, Zhou G. (2014) Chemotherapy-induced myeloid suppressor cells and antitumor immunity: the Janus face of chemotherapy in immunomodulation. OncoImmunology. 3(8):e954471.

Wei JX, Lv LH, Wan YL, Cao Y, Li GL, Lin HM, Zhou R, Shang CZ, Cao J, He H, Han QF, Liu PQ, Zhou G, Min J. (2014) Vps4A functions as a tumor suppressor by regulating the secretion and uptake of exosomal microRNAs in human hepatoma cells. Hepatology. Dec 12. doi:10.1002/hep.27660.

Lu X, Ding ZC, Habtesion T, Yu M, Zhou G. (2015) Alkylating agent melphalan augments the efficacy of adoptive immunotherapy using tumor-specific CD4+ T cells. J Immunol. 194(4):2011-21.

Paschall AV, Zhang R, Qi CF, Bardhan K, Peng L, Lu G, Yang J, Merad M, McGaha T, Zhou G, Mellor A, Abrams SI, Morse HC 3rd, Ozato K, Xiong H, Liu K. (2015) IRF8 Expressed in T Cells and Tumor Cells Regulates GM-CSF Expression to Control Myelopoiesis and Myeloid-derived Suppressor Cell Differentiation. J Immunol. 194(5):2369-79.