Research

Past Contributions to Cancer Immunology

Within the last five years, my team has made the following major contributions to the tumor-treatment and tumor-immunology fields.

These studies are highly significant and translatable, and have the potential to change clinical practice using oncogenic receptors in antitumor therapy (for example, HER2/neu+ tumors can be treated with a combination of radiation plus anti-HER2/neu–specific Abs, bispecific Abs, or an Ab–cytokine fusion protein after IR). Collectively, they have opened up new fields of combination treatment that maximize the efficacy of both conventional therapies and immunotherapy. Continued work in this direction is essential if immunotherapy is to be integrated successfully into current standard-of-care protocols.

Ablative irradiation and innate and adaptive immune responses

The therapeutic effect of ablative irradiation (IR) depends on innate and adaptive immune responses: bridging DNA damage to DNA sensing for increased CTL-mediated tumor regression. Local ablative IR has long been thought to cause DNA damage and directly kill tumor cells, leading to control of tumor growth. We have unexpectedly observed that local ablative radiation–mediated tumor regression mainly depended on type I IFN, DC, and CD8+ T cells within the immune system. We has now revealed that cytosol cGAS-STING in DCs can sense tumor DNA to trigger IR-induced immunity. Better understanding of radiation-mediated tumor regression will inform the design of immunotherapy trials after IR.

Lee Y et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: Changing strategies for cancer treatment. Blood. 114(3):589-95, 2009. PMCID: PMC2713472.
Ablative radiation can control tumor growth via DNA damage and mitotic crisis. Our study revealed that T cells are also essential for tumor control after high IR doses. Moreover, while subsequent chemotherapy impaired IR-induced immunity, subsequent immunotherapy greatly reduced IR-associated resistance.
 
Burnette BC et al. The Efficacy of Radiotherapy Relies Upon Induction of Type I Interferon-Dependent Innate and Adaptive Immunity. Cancer Res. 71:2488-2496, 2011. PMCID: PMC3070872.
This is the first paper showing the essential role of type I IFN in IR-mediated tumor regression and IR-initiated immunity, leading to a better understanding of the important role of innate and adaptive immunity in IR-mediated tumor regression. Our data suggest that IR-induced DNA damage may promote type I IFN dependency for cross-priming and T cell immunity, similar to viral DNA.
 
Liang H et al. Radiation-Induced Equilibrium Is a Balance between Tumor Cell Proliferation and T Cell-Mediated Killing. J Immunol. 190:5874-81, 2013. PMCID: PMC3660450.
Local ablative IR induces tumor dormancy or stable disease. Although most reports focused on how high doses of IR induced senescence, endothelial damage, or mitotic crisis, we demonstrated that the dynamic balance between tumor-cell proliferation and T cell–mediated killing of tumor cells could explain this IR-induced equilibrium.
 
Deng L et al. Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 124(2):687-95, 2014. PMCID: PMC3904601.
Repeated IR can induce IR resistance, while only 20% patients respond to anti–PD-L1 antibody. Our study showed that IR-induced PD-L1 expression on tumor cells led to tumor-cell resistance to T cell–mediated killing, allowing early relapse. Since subsequent PD-L1 blockade led to complete cure in well-established tumors, this study presented a new strategy to increase control of radio-resistant cells and broaden host responses to anti–PD-L1.
 
Deng L Liang H, Xu M, Yang X, Burnette B, Arina,A Li, X Mauceri H, Beckett M, Darga T, Huang,X. Gajewski TF, Chen Z, Fu, YX (corresponding author) and Ralph R. Weichselbaum. Radiation-triggered cytosolic DNA sensing pathway bridges Type I interferon-dependent Innate and adaptive immune responses. Immunity. 41(5):843-52, 2014
IR induced DNA damage is closely associated with IR-induced death of tumor cells. We have now revealed that such DNA damage might provide excess DNA to sense cytosolic DNA sensing pathway for IFN production and cross-priming.   STING activator can be a very potent drug to activate DC to enhance radiation sensitivity.
 

Innate and adaptive immunity in tumor regression

Oncogenic receptor blockade by antibodies (Abs), such as Herceptin, can induce apoptosis, leading to control of tumor regression; however, relapse often occurs even after prolonged and costly treatment. My team unexpectedly observed that targeting tumors with such antibodies controlled tumor growth in a T cell–dependent manner. These findings have helped to revise and enhance our understanding of the mechanism-of-action for anti–oncogenic receptor Abs and rejuvenated the field for properly arming antibodies with various cytokines that can activate anti–tumor-specific T cell responses through increasing cross-priming of tumor antigens.

Park S et al. The therapeutic effect of anti-HER2/neu antibody depends on both Innate and adaptive Immunity. Cancer Cell. 18:160-70, 2010. PMCID: PMC2923645.
We observed that targeting tumors with such antibodies can control tumor growth in a T cell–dependent manner. Specifically, Ab blockade induces stress signals on oncogenic-dependent tumors, leading to MyD88-dependent innate and adaptive immune responses.
 
Yang X et al. Targeting the tumor microenvironment with interferon-b bridges innate and adaptive immune responses. Cancer Cell. 25(1):37-48, 2014. PMCID: PMC3927846.
From our initial observation that the lack of sufficient IFN signaling prevented effective immune recognition and tumor rejection, we linked anti-EGFR or anti-neu Abs to type I IFN to create the next generation of armed Abs and indeed observed a much more potent effect on tumor growth than Ab alone through increased cross-priming of specific CTLs.
 
Mortenson E et al. Effective anti-neu initiated anti-tumor responses require the complex role of CD4+ T cells. Clin Cancer Res. 19(6):1476-86, 2013. PMCID: PMC3602165.
CD4+ T cells play a unique and essential role for anti-neu antibody–mediated tumor regression.
 
Yang X et al. Cetuximab-mediated Tumor Regression Depends on Innate and Adaptive Immune Responses. Mol Ther. 21(1):91-100, 2013. PMCID: PMC3538305.
We have developed a new, clinically relevant model using human EGFR–dependent, human tumors with immune reconstitution and observed that cetuximab-mediated tumor regression was dependent upon innate and adaptive immune responses.

Recruiting and activating DC and lymphocytes in immunotherapy

The lack of sufficient tumor-infiltrating T cells (TILs) has been shown to prevent effective immunotherapy, as more than 60% clinical cancer samples exhibit very few TILs and thus are resistant to various immunotherapies such as anti–PD-L1 or CTLA4 Ab. Thus, creating a microenvironment that can attract enough DCs and T cells to sufficiently control tumor growth may greatly improve current immunotherapy. Under my guidance as the Principal Investigator, my team revealed that proper expression of LIGHT (TNFSF14) inside tumor tissues could potently attract and reactivate DCs and T cells within the tumor microenvironment, and we have recently extended these studies to develop anti-EGFR and -HER2/neu Abs armed with LIGHT for improved targeting of LIGHT to tumors.

Yu P et al. Priming of naïve T cells inside tumors leads to the eradication of established tumors. Nat Immunol. 5:141-9, 2004.
This is the first paper demonstrating that increased LIGHT expression inside tumor tissues allows for recruitment and activation of DC and naïve T cells inside tumor tissues, leading to tumor rejection.
 
Yu P et al. Intra-tumor depletion of CD4+ cells unmasks tumor immunogenicity leading to rejection of established tumor. J Exp Med 201:779–791, 2005.
This is the first report that intra-tumor Treg is essential to suppress ongoing immune responses.
 
Fan Z et al. NK-cell activation by LIGHT triggers tumor-specific CD8+ T-cell immunity to reject established tumors. Blood. 107:1342-51, 2006.
This is the first paper showing that LIGHT can activate NK cells inside tumor tissues to stimulate and magnify CTL responses.
 
Wang Y et al. Promoting Immune Responses by LIGHT in the Face of Abundant Regulatory T Cell Inhibition. J Immunol. 184(3):1589-95, 2010. PMID:20042587.
This is the first study showing that LIGHT-activated T cells can resist Treg-mediated suppression.
 
Yu P et al. Targeting the primary tumor to generate CTL for the effective eradication of spontaneous metastasis. J Immunol. 179:1960-8, 2007.
We show that targeting tumor tissues with adenovirus expressing LIGHT induces more effective recruitment and activation of CTL in local tumor tissues. Those T cells can also migrate and home into distal tumor tissues or metastasis, leading to eradication.
 
Tang H, Wang Y, Chlewicki LK, Zhang Y, Guo J, Liang W, Wang J, Wang X, Fu YX. Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade. Cancer Cell. 2016 29(3):285-96.