Cancer is a disease that develops in a stepwise fashion as a heterogeneous population of cells slowly overcomes the regulatory circuits that normally bar cells from limitless replicative potential. One such regulatory pathway is that of immune surveillance. There is now good evidence from mouse models that the immune system places pressure on the development of cancer and can maintain it in an occult state. Cytolytic T lymphocytes (CTLs) and their effector proteins have been shown to be at least partially responsible for this effect. The clinical symptoms of cancer, however, arise after the tumor has established an immunosuppressive environment that is able to circumvent these pressures. Therapies targeting this pathway have sought to prime and reinvigorate CTL responses using viral vectors or by loading autologous dendritic cells (DCs) with tumor-associated antigens and re-injecting them into the patient. These therapies have shown efficacy in some patients, demonstrating the feasibility of such a protocol. Although feasible, success rates have been disappointing and current work seeks to target antigens to the relevant DC subsets in vivo for efficient generation of antitumor CTLs. The CD8alpha DC subset is a promising candidate, given its ability to acquire exogenous antigens for presentation to CTLs, a process termed cross-presentation. This unique ability has, at least in part, been attributed to its ability to endocytose apoptotic cells. These two characteristics, however, have been difficult to mechanistically link since the molecular requirements for this engulfment are not understood. It is generally believed that CD8alpha DCs express a receptor for phosphatidylserine (PS), a prominent feature of apoptotic cells, which could explain this phenomenon. Our preliminary in vitro experiments demonstrate that T cell immunoglobulin domain and mucin doman-4 (TIM-4), a PS receptor, is preferentially expressed by CD8alpha DCs upon maturation and that inhibition of TIM-4 function leads to inefficient uptake of apoptotic cells and defective cross-presentation of these cell-associated antigens.
Aim 1 will establish whether and to what extent TIM-4 contributes to cross-presentation of apoptotic cell-associated antigens and subsequent generation of CTL immunity in vivo.
Aim 2 will seek to test whether TIM-4 can be used to target antigens to CD8alpha DCs for efficient cross-presentation and subsequent rejection of tumors. If our hypotheses can be proven correct, these experiments will add to our understanding of the molecular requirements for immunosurveillance and provide a possible basis for cancer treatment.

Public Health Relevance

Vaccines to treat cancer seek to cause tumor destruction through activation of tumor- reactive cytotoxic T lymphocytes (CTLs). The success of these strategies has been hampered by a limited understanding of the antigen presentation pathways that lead to CTL activation. This study seeks to examine the mechanisms by which antigens are captured for presentation to CTLs and how this knowledge may be implemented to more efficiently generate tumor-destroying CTLs.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F09-A (08))
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Schmidt, Michael K
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Harvard Medical School
Schools of Medicine
United States
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