Postdoctoral Fellow Harvard Med. Sch., United States
Introduction/Rationale: Cancer originates from a single or a few cells that acquire oncogenic mutations, leading to uncontrolled proliferation and subsequent transformation. Initially, altered pre-cancerous cells are susceptible to immune surveillance. To grow into tumors, transformed cells must develop mechanisms of immune evasion. This bottleneck process is a dynamic equilibrium where mutated cells proliferate and acquire further mutations while the immune system attacks them. Importantly, the mechanisms by which these subsequent mutations promote immune evasion and how the early immune pressure shapes cancer’s mutational landscape remains poorly understood.
Methods: To uncover mechanistic studies of immunoediting during tumor initiation, we need the use of pre-clinical models that resemble disease progression and in which we have control of tumor induction. Our lab has recently stablished a mouse model in which tumor formation is controlled by intraductal injection of CRE to mediate Brca1 heterozygous deletion recapitulating human disease (Li et al. Nature Genetics 2024) in adult mice. The intraductal model can also be used with CRISPR technology to induce breast cancer common alterations in the mammary epithelial cells. This model allows for tight control of tumor initiation and the genetic alterations introduced.
Results: Using these new models of breast tumor initiation, we will investigate 1) the immune infiltrates in early tumor lesions, 2) mutations leading to immune evasion and 3) how the immune pressure shapes the mutational landscape.
Conclusion: Understanding these processes has the potential to generate immune based therapies to prevent cancer in high-risk individuals. Understanding the process of tumor initiation in an immune context will establish the basis to understand how tumors are shaped and how they generate immune exclusion or immunosuppressive microenvironments to avoid immune recognition.
