Immune Evasion Mechanisms in Neuroblastoma
Abstract
Scientific Objective and Rationale: Despite intensive treatment that includes chemotherapy, surgery, radiation, and stem cell transplantation, patients with MYCN-amplified neuroblastoma, a tumor of the nervous system, have a very low survival rate, and once the tumor relapses, the number of curative treatment options dwindles to zero. One of the new and exciting treatment strategies for cancer is immunotherapy. Indeed, some patients with neuroblastoma respond to the anti-GD2 antibody, dinutuximab. However, the response to other forms of immunotherapy, such as checkpoint blockade, has not been encouraging in neuroblastoma, mainly because the tumor cells have devised strategies to evade immunotherapy. The immune system acts as the body’s defense against cancer by recognizing and attacking cancer cells. However, cancer cells, especially MYCN-amplified neuroblastomas, have devised strategies collectively called “immune evasion,” to thwart these protective mechanisms, thus making it difficult for immunotherapies to be fully effective. We have observed that MYCN amplification is associated with genes that evade the immune response, but exactly how MYCN does this is not known. We aim to understand how the MYCN gene can cause tumor growth by shutting off protective immune mechanisms. To achieve this goal, we will use a novel mouse-human model that we generated and which overcomes a major obstacle to the accurate study of immune regulation in cancer – the lack of animal models of cancer with intact immune systems. Studies thus far have used mice with suppressed immune systems that do not faithfully mimic the tumor environment. We will use our novel model in which human neuroblastoma precursor cells overexpressing the MYCN gene are introduced into mouse embryos – these human-mouse chimeric animals develop human neuroblastomas despite their intact immune systems. Moreover, the tumors show evidence of an active immune response, thus making it an excellent model to study immune evasion mechanisms. We will use our model to identify the protective immune mechanisms that are abolished by amplified MYCN, with a view to preventing or overcoming these challenges to the implementation of novel immune therapies. Ultimate Applicability of the Research: Accomplishment of our research objectives will help to improve outcomes for high-risk neuroblastoma patients by (1) devising strategies to improve the effectiveness of currently used immunotherapies to prevent recurrence and achieve a complete cure, (2) testing novel immunotherapies in animal models with intact immune systems, and (3) identifying novel targets that can be leveraged for immunotherapy. In the short-term, our research will advance the field of cancer research by providing evidence to substantiate testing strategies to prevent immune evasion in patients with MYCN-amplified neuroblastoma. We will also identify predictors of immune evasion in patients with high-risk neuroblastoma without MYCN amplification in their tumors. Our long-term goal is to establish chimeric models of each human tumor, by growing primary tumor cells from neuroblastoma patients in animals with intact immune systems, so that we can assess whether the immune responses in these animals correspond to those in the donor patient. This will allow us to not only correlate clinical phenotypes with our experimental readout and to define genetic abnormalities that increase the risk for progressive neuroblastoma development due to immune evasion, but also to identify different combinations of effective chemo- and immune-based therapies on a patient-by-patient basis. Fiscal Year 2019 Peer Reviewed Cancer Research Program Military Health Focus Area: Our proposal will address gaps in cancer treatment that affect the general population and have a particularly profound impact on the health and well-being of military Service members, Veterans, and their beneficiaries. No child is exempt from developing NB, includi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010780
Entities
People
- Rani George
Organizations
- Dana–Farber Cancer Institute
- United States Army