Despite significant efforts to elucidate the mechanisms by which immune cells are capable of recognizing and interacting with tumor cells, little is known about the decision-making process that distinguishes between tumor promotion and tumor rejection via anti-tumor immune responses. We hypothesize that the outcome of immunological tipping point results from the holistic behavior of the tumor-immune network. Therefore, discerning the characteristics of pro-tumor and anti-tumor network states will require a systems biology approach capable of simultaneously integrating measurements of the activity of different immune cell and tumor cell populations. One such approach developed in our laboratory is mass cytometry, a high-dimensional proteomic technology with single-cell resolution. Mass cytometry enables the identification and enumeration of cell populations as well as the interrogation of their cellular behavior, for example by quantifying the levels of actie cell signaling proteins. Therefore, we propose the application of mass cytometry to discern the principal features that govern the activity within the tumor-immune network. By utilizing genetically-engineered mouse models of cancer, which reflect histologic and genomic hallmarks of human tumors, we will determine which immune cell populations alter their behavior at the earliest stages of tumorigenesis. We will use biochemical cell signaling and cell cycle as a metric of the cellular state, as these processes form the core information processing and integration machinery of the cell. By interrogating the tumor-immune network during tumor formation via mass cytometry, we will identify the core functional modules that organize this complex cellular system. In order to discern these coordinated processes, we will apply novel single-cell analytical algorithms developed in our laboratory capable of displaying high-dimensional data in a 2D plane and categorizing cellular behavioral changes into co-regulated functional cassettes. The results of these experiments will determine which cellular programs govern immune reactivity to nascent tumors, results that we will further validate via genetic and pharmacological intervention. Additionally, new types of cancer therapies targeting the immune system, commonly referred to as immunomodulatory therapies, have recently generated significant interest. However, little remains known about the immune system states that these therapies induce in order to drive anti-tumor immunity. We will therefore extend our analysis of the tumor-immune network to a model of immunomodulatory therapy for cancer, revealing the state of the network that permits tumor rejection. These experiments will define a road map to an effective anti-tumor immune response, revealing and defining opportunities to consistently achieve these results in the clinical setting. We therefore believe that these studies have the potential to transform cancer therapy by discerning the behavioral features of the tumor- immune network that regulate the immunological tipping point against cancers.
While the immune system has the potential to recognize and kill tumor cells, it often remains in check during tumor development, even promoting the development of many cancers. Our studies aim to understand the guiding principles behind this decision-making process, which can result in tumor promotion or tumor rejection via anti-tumor immune responses. By defining these features, we will provide a road map for activating the immune system against tumors, enabling the design of new therapies that could revolutionize cancer treatment in the clinic.
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| Spitzer, Matthew H; Carmi, Yaron; Reticker-Flynn, Nathan E et al. (2017) Systemic Immunity Is Required for Effective Cancer Immunotherapy. Cell 168:487-502.e15 |
| Carmi, Yaron; Prestwood, Tyler R; Spitzer, Matthew H et al. (2016) Akt and SHP-1 are DC-intrinsic checkpoints for tumor immunity. JCI Insight 1:e89020 |
| Spitzer, Matthew H; Nolan, Garry P (2016) Mass Cytometry: Single Cells, Many Features. Cell 165:780-91 |
| Carmi, Yaron; Spitzer, Matthew H; Linde, Ian L et al. (2015) Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity. Nature 521:99-104 |
| Spitzer, Matthew H; Gherardini, Pier Federico; Fragiadakis, Gabriela K et al. (2015) IMMUNOLOGY. An interactive reference framework for modeling a dynamic immune system. Science 349:1259425 |
