The Schaue Lab
We are small lab with a not so small mission. Most of what we do centers on the fundamental question of how irradiated normal tissues and cancers interface with the immune system and what this means for tumor immunity, normal tissue toxicity, and premature aging. Cells differ in intrinsic radiosensitivity, and this is a major reason for therapeutic failure. Since the immune system is in the field, radiation shapes the balance within the different immune cell subsets. At the same time, radiation-induced tissue damage releases danger signals that feed into common immune signaling pathways to generate responses. The consequences are multifaceted, ranging from altered anti-tumor immunity, tissue inflammation, and, in extremis, skewed hematopoietic output. The fact is that radiation exposure, even locally delivered, has systemic effects and immune responses are generated that evolve over time.
Our approach comes in many flavors. We study tumor-specific immune responses following radiation therapy (RT) in mice and men and have documented a regulatory signature that is both myeloid and lymphoid in nature and is an evolutionary conserved tissue healing response that is immunosuppressive and limits the effectiveness of currently FDA-approved immune-modulating agents. We also look for novel radiation biomarkers and avenues for mitigation of acute and late radiation syndromes. We have explored effects on the redox rheostat, immunoproteasomes, and antigen presentation. Ultimately, the goal is to differentially modulate normal tissue and tumor responses to radiation exposure so as to improve outcome.
Dörthe Schaue, PhD, PI
Jacob F. Hack, BSc, Staff Research Associate
Yuyuan (Peter) Guo, PhD, Staff Research Associate
Josephine A. Ratikan, MSc, Staff Research Associate
Tracey Huynh, Undergraduate Student
Bill McBride, DSc, Mission Compass
Recent Past Members:
Mi-Heon Lee, PhD, Project Scientist
Mirna Kalayjian, BSc, Staff Research Associate
Jean-Philippe Nesseler, MD, Postdoctoral Scholar
Dr. Ekambaram Ganapathy, PhD, Project Scientist
Duang Ratanachan, BSc, Staff Research Associate
Zitian (Andy) Wang, Undergraduate Student
Christine Nguyen, Undergraduate Student
Our Current and Past Research
Our work spans clinical translational studies aimed at the integration of immunotherapy into the radiation oncology clinic to preclinical radiation biomarker investigations and normal tissue damage mitigation. We use many murine systems, human-mouse hybrid models, and patient’s samples and draw from a toolbox of immunological assays such as multi-color flow cytometry, ELISPOT, TCRseq, adoptive cell transfer and loss of function genetic mouse models in concert with proven radiobiology techniques.
Radiation mitigation & normal tissue responses to radiation: The immune system modulates expression of radiation-induced acute and late tissue damage. We demonstrated that late radiation organ damage integrates signals from a prematurely aged immune system with persistent myeloid skewing in the bone marrow that feeds persistent inflammation and immunosenescence. We have shown that activation of the myeloid system is critical for mitigation of hematopoietic ARS, but that a later permanent shift of the immune system occurs towards myelopoiesis with inflammatory consequences. This is a topic of ongoing work, but we have shown that chronic radiation-induced inflammation can lead to multiple organ disease and life shortening. We extensively study how radiation engages complex networks of cytokines, redox, innate and adaptive immune cells that leads to failure of regeneration, fibrosis, acute and chronic damage and carcinogenesis. Understanding how radiation impacts inflammation and immunity is critical if we are to effectively manipulate these forces for benefit in radiation oncology treatments and in radiation accidents.
Myeloid cells are central players in radiation tissue responses: Our interest in myeloid cells stem from their role in inflammation and immunity. Myeloid cells are the first responders and are involved at virtually every step of the pathological tissue response to radiation. They interface between radiation damage and both acute and chronic late effects by virtue of sensing persistent DNA damage and DAMPs as danger signals. We discovered the striking emergence of a novel immature subpopulation of myeloid cells after irradiation that is not normally evident in peripheral organs but quickly mobilized from bone marrow myeloerythroid progenitor cells and persists as the immune balance is skewed towards myelopoiesis. Our goal is to illuminate the fate and function of these myeloid cells.
Radiation Biomarker Development: One major NIH-funded project currently ongoing looks at changes in circulating miRNA signatures in irradiated mice as a biodosimeter able to identify patterns of responses that predict radiation-induced late organ injury. We do this together with our collaborators at ChromoLogic LLC. The study has broad relevance to acute and chronic radiation effects and it epitomizes the complex interaction between radiation-damaged tissues and immune homeostasis.
Antigen processing and presentation and the initiation of antitumor immune responses: We were the first to report that targeting the pathways involved in antigen uptake, internal routing and processing can shape the way radiation damage is translated into effective tumor immunity. We demonstrated that radiation matures dendritic cells into antigen presenting cells. Most recently, we have shown that ionizing radiation reprograms the antigen processing and presenting machinery. This includes inducing immunoproteasome subunits that process MHC class I tumor antigens and immune eradication of tumors following RT. This novel observation is a key mechanism for radiovaccination that opens new avenues for radiotherapeutic intervention.
Radiation-induced tumor immunity: RT in cancer patients alters their immune system in a way that can affect treatment success. Unfortunately, our understanding is still very limited. We are interested in how radiation-induced tumor cell death translates to immunity, how we can measure this in vivo, and how the immune balance is affected by differences in treatment options, especially since we showed that RT may have superior immune adjuvanticity when given at higher-dose per fraction. We also found that some patients with colorectal and prostate cancer increase their level of circulating tumor-specific T cells when treated with RT, although there is a simultaneous rise in regulatory T cells that may limit their efficacy. We recently reported in a first-of-its-kind study the radiation-induced changes in the intratumoral immune landscape in human prostate tumors, and in a novel, multi-institution, Phase I trial that anti-TGFb (fresolimumab) re-directs the tumor-host relationship towards tumor immunity and enhanced T memory cells in advanced breast cancer. The importance of anti-TGFb in blunting tumor immunity may also be why tumor burden is such a critical factor when combining RT and immunotherapy, as we recently demonstrated.
Regulatory T cells (Tregs) control radiation-induced tumor immunity and tissue damage: We have evidence that tight control by Tregs limits excessive immune activation and favors immune evasion. Knowing how RT drives the Treg lineage is essential if immune intervention strategies are to be safely and effectively used in conjunction with clinical RT. If radiation-induced killing of cancer can be translated into better tumor immunity without increasing normal tissue damage, the probability of achieving control of local and micrometastatic disease will increase.
In vivo imaging of radiation-induced tumor immunity: RT combined with immunotherapy can yield promising results, but our ability to monitor intratumoral responses is very limited. In collaboration with Dr. Anna Wu at City of Hope we have developed new tools to interrogate the tumor-host interface by noninvasively imaging CD8 cytotoxic T cells using engineered antibody fragments and immunoPET. We are also examining whether calreticulin immunoPET can provide an early noninvasive biomarker of immunogenic cell death and predict subsequent CD8 T cell infiltration in tumors.
Nickols et al. (2021) The intraprostatic immune environment after stereotactic body radiotherapy is dominated by myeloid cells. Prostate Cancer Prostatic Dis
Nesseler et al. (2020) Tumor Size Matters-Understanding Concomitant Tumor Immunity in the Context of Hypofractionated Radiotherapy With Immunotherapy. Cancers
Schaue D. and McBride W.H. (2020) Flying by the seat of our pants: is low dose radiation therapy for COVID-19 an option? Int J Radiat Biol
Rogers et al. (2020) Identification of miRNA signatures associated with radiation-induced late lung injury in mice. PLoS One
Micewicz et al. (2019) The Aftermath of Surviving Acute Radiation Hematopoietic Syndrome and its Mitigation. Radiat Res
Formenti et al. (2018) Focal Irradiation and Systemic Transforming Growth Factor β Blockade in Metastatic Breast Cancer. Clin Can Res
Micewicz et al. (2017) 4-(Nitrophenylsulfonyl)piperazines mitigate radiation damage to multiple tissues. PLoS One
Ratikan et al. (2013) Chloroquine engages the immune system to eradicate irradiated breast tumors in mice. Int J Radiat Oncol Biol Phys.
Schaue et al. (2008) T-cell responses to survivin in cancer patients undergoing radiation therapy. Clin Cancer Res