PQB - 3 What molecular and cellular events determine whether the immune response to the earliest stages of malignant transformation leads to immune elimination or tumor promotion? Background: The immune system plays conflicting roles in tumor development, having both the capacity to eliminate transformed cells, as well as the ability to promote their tumorigenic potential. However, the molecular and cellular events that regulate the immunological tipping point between tumor elimination and tumor promotion are not clear. In part, this is due to the difficulty in assessing the earliest time points when newly transformed cells first interact with the surrounding stroma, including the host immune system. Critical events at this stage can determine whether a pre-emergent tumor is either eliminated by the immune response or allowed to progress, in some instances with the support of immune cells. Recent reports have suggested that within hours after an oncogenic event, transformed cells secrete danger signals that attract innate immune cells that support tumor cell expansion. Thus, even before there is a tumor microenvironment (and in particular an immunosuppressive tumor microenvironment) the immune system is alerted to the presence of a potential cancer by tumor-derived danger signals. All along the cancer continuum, from a single transformed cell to a metastatic cancer, it is likely that distinct tumor-derived danger signals are generated and sensed by the immune system. Importantly, the nature of the immune response to these various danger signals could have profound consequences in determining whether tumors are eliminated or allowed to progress. Encouraging studies focused on the earliest time points of carcinogenesis and determining how tumor-derived danger signals influence the anti-tumor immune response could have profound implications for cancer prevention and improving immunotherapeutic approaches to eliminate cancer. Feasibility: An important prerequisite for studies in response to this question will be the selection of appropriate systems to study the immune response to the very first stages of cells transformation. Genetically engineered mouse models might provide a good system to being such studies or there may be some well understood human tumor development system that could be used. Characterization of well-known immune response mechanisms at these earliest stages may provide a useful starting point for studies. These stages may also lend themselves to high-throughput profiling or other “omic”-style studies to help characterize these events and provide potential new hypotheses for study. Implications of success: Understanding the earliest types of immune response to the emerging tumor cell promises to be one of the best points to influence the course of malignancy development. The ability to both push the immune response towards elimination or to block any enhancement of tumor development could be used to identify new target for therapy or for prevention. |
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