Why endogenous immune responses with demonstrable tumor associated antigen (TAA)-specific CD8 + T cells fail to eradicate tumors remains a significant and unresolved question. A related and potential more important question is why T cell-mediated or dendritic cell (DC)-based immunotherapy generally fails to induce robust and durable anti-tumor immunity in patients. Recent studies have described regulatory T cells, of which theCD4+CD25 + subset (CD4 + Tr) is best characterized, which physiologically suppress autoimmune T cell responses and maintain peripheral tolerance. Anti-tumor immunity is thought to be an """"""""autoimmune response,"""""""" we thus propose to examine the function and generation of human CD4 + Tr tumor infiltrating lymphocytes from the ascites of ovarian cancer patients in a novel in vivo NOD/SCID model.
Our specific aims are:
Aim 1. To test our hypothesis that tumor CD4 + Tr inhibit TAA-specific immunity in vivo. Little is known of CD4 + Tr in the context of human tumors. We observed a substantial amount of CD4 + Tr in malignant ascites inpatients with ovarian cancers. By adoptively transferring tumor CD4 + Tr to human-NOD/SCID chimera, we will determine their effects on TAA-specific CD8 + T cell immunity in vivo. We hypothesize that tumor CD4 +Tr cells suppress TAA-specific CD8 + T cell responses. We predict that blockade of CD4 + Tr generation or/and regulatory function could be a potential approach for cancer immunotherapy.
Aim 2. To test our hypothesis that tumor macrophages induce CD4 + Tr cells in vivo. Generation of Tr cells is one of the central questions in immunology. Antigen presenting cells (APC) are thought to be important in Tr cell generation. We showed that tumor macrophages induced suppressive TAA-specific CD4 + Tr in vitro, and B7-H1 was critical for CD4 + Tr induction. By adoptively transferring human T cells to human-SCID mouse chimeras, and stimulating T cells in vivo with tumor macrophages, we will determine the in vivo generation of tumor CD4 + Tr. We hypothesize that tumor macrophages induce CD4 + Tr cells and blockade of B7-H1 could block CD4 + Tr cell generation in vivo. Thus, blocking B7-H1 could be a potential approach for cancer immunotherapy.
Aim 3. To test our hypothesis that myeloid DC (MDC) plus IL-2 can override the regulatory effects of CD4 +Tr cells in vivo. MDC induce TAA-specific effector T cells conducting anti-tumor immunity. Tr cells may suppress anti-tumor immunity. Early clinical trials with TAA bearing MDC have only demonstrated modest clinical benefits predicted from preclinical models. Can CD4 + Tr be functionally reversed or abated in vivo by concurrent stimulation of MDC with or without IL-2? By in vivo stimulating tumor CD4 + Tr with autologous MDC plus IL-2, we will determine the in vivo functional identity and reversibility of tumor CD4 + Tr. We hypothesize that MDC plus IL-2 are beneficial to tumor immunity by modifying the regulatory function ofCD4 + Tr cells. We predict that MDC plus IL-2, not MDC alone may be a strategy for treating cancer patients.
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