URPP Fellow: Nicolas Nunez
Conventional cancer therapies rely on targeting the malignant cells through surgery, radiation and/or chemotherapy. At this point in time, it is unlikely that such strategies will provide additional therapeutic benefit and in particular treatment resistant solid-tissue cancers require novel approaches. Immune subversion by cancers is by now well documented and accepted and reversal of this process as well as activation of anti-cancer immunity is likely the most promising strategy to combat cancer in the years to come. The success of check point blockers in metastatic refractory melanoma highlights the potential of cancer immunotherapy to not only halt cancer progression, but also to cure established malignancies. One puzzling aspect is the relatively small percentage of patients, which show long-term progression free survival. It appears that even strong anti-tumor immune responses fail to penetrate the tumors.
Cancers not only contain transformed cells, but also actively shape their microenvironment, which is made up of non-transformed stromal, endothelial and immune cells. The impact of such cells on tumor progression, the formation of metastases, and the response to standard or immune therapies is largely unknown but of great interest and an emerging field of research. In the context of immunotherapy for example, between 20 and 40% of patients respond to checkpoint blockade, implicating that a large percentage of patients still do not respond. Suboptimal or absent responsiveness in those patients is also reported for other treatments, including standard therapies. We propose that the tumor microenvironment influences the clinical response to treatment. In particular, we think that the tumor-associated innate leukocyte compartment, which makes up the majority of the non-malignant cells in a tumor, impacts on the adaptive anti-tumor response in most patients and as such, sets the course for response to therapy.
Here, we wish to delve deeper into studying this major component within a tumor - the innate immune system - in a multi-dimensional and unbiased way using state-of-the-art technologies such as CyTOF and bioinformatics, and making use of appropriate mouse models of disease as well as unique genetically characterized patient-derived tumor samples and live tumor cells deposited in our URPP tumor cell biobank.
In Aim 1 we will further employ the technology for multi-dimensional and unbiased analysis of immune cells. Using this approach, we will characterize the innate immune compartment, including myeloid cells and innate lymphocytes (ILCs), in growing tumors using preclinical models that include injected cell lines, autochthonous tumors, models for spontaneous metastasis upon surgical resection of the primary tumor and xenografted human tumors.
In Aim 2 we will characterize changes in the innate, tumor-associated compartment that occur as a consequence of radiotherapy, kinase inhibitors or checkpoint blockade but also analyze the impact of changed levels of pro-inflammatory molecules such as IL-1b, IL-6, HMGB1, complement and alarmins. The results may help to define an innate signature that predicts the response to therapy, but also may reveal pathways that can be targeted to make a therapy more efficient.
In Aim 3 we will use the knowledge acquired in Aims 1 and 2 to analyze the innate compartment in genetically-characterized patient-derived tumor samples deposited in our URPP tumor cell biobank in an unbiased, multi-dimensional fashion to define correlates and predictors for disease progression and response to therapy.
We anticipate that this project will result in better understanding of cellular and molecular mechanisms within the tumor microenvironment, which determine the outcome of cancer therapies. Moreover, it may allow us to improve existing therapies by controlled activation or elimination of certain components of the innate compartment.