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Reversal of Tumor-Induced Immune Suppression
Background: Breast cancer patients whose primary tumors have been successfully removed but who have metastatic disease are a prime target population for immunotherapy. The therapeutic efficacy of immunotherapy is entirely dependent on the patient’s ability to respond to tumor antigens. Although primary, solid tumors are known to cause immunosuppression, there is little information on the immunocompetence of post-surgery individuals with latent or active metastatic disease.
Objective/Hypothesis: Our goal is to identify a “window” of time after surgical removal of primary mammary carcinoma during which individuals with metastatic disease are minimally immunosuppressed. Our hypothesis is that although tumor-bearing individuals are immune suppressed, this suppression can be reversed if primary tumor is surgically removed, even when metastatic disease is present.
Specific Aims: We will identify the therapeutic “window” by evaluating the dominant mechanisms that mediate immune suppression, through 3 aims: (1) Individuals with primary tumors are tolerant to their tumor antigens. Whether tolerance persists after primary tumor is removed is unknown. We will assess tolerance in post-surgery individuals. (2) CD4+CD25+ T regulatory cells (T regs) are potent down-regulators of tumor-specific immunity. It is unknown whether these cells persist after surgical removal of primary tumor. We will determine if post-surgery individuals with metastatic disease retain CD25+ T regs. (3) Myeloid-derived suppressor cells (MSC) block tumor-specific T cell activation and accumulate in animals and patients with primary tumors. The kinetics of MSC development relative to metastatic tumor burden is unknown. We will assess MSC levels in post-surgery individuals with metastatic disease.
Study Design: Primary mammary tumors will be surgically removed from BALB/c mice with metastatic 4T1 mammary carcinomas, a mouse tumor whose progression is similar to human breast cancer. As metastatic disease progresses, mice will be tested for tolerance to tumor antigens, MSC cell activity, and CD4+CD25+ T reg activity. Metastatic disease will be quantified and plotted relative to immune function.
Potential Outcomes and Benefits. These studies will determine if immune suppression is sufficiently reduced in individuals with metastatic disease so that they are candidates for immune therapy. Demonstrating the existence of a therapeutic “window” will support the feasibility of immunotherapy and may clarify when individuals will be maximally responsive to immune-based therapies.
Background: Novel immunotherapy strategies are being developed for the treatment of metastatic mammary cancer. The guarded success of some of these innovative approaches is providing hope that more effective immunotherapies can be developed. The therapeutic efficacy of immunotherapy is entirely dependent on patients’ ability to immunologically respond to tumor antigens. Although primary, solid tumors are known to be potent inducers of immune suppression, there is little information on the immune competence of post-surgery individuals with latent or active metastatic disease.
Objective/Hypothesis: We hypothesize that surgical removal of a primary mammary tumor reduces tumor-induced immune suppression and opens a “window” of time during which individuals are minimally immunosuppressed and maximally responsive to immunotherapy.
Specific Aims: We will identify the therapeutic “window” by completing the following specific aims using a mammary tumor whose progressive growth in mice is very similar to the progression of human breast cancer. 1) Determine if individuals are “tolerant” to their tumor markers (“antigens”) and therefore do not make an immune response against it. 2) Determine if a population of inhibitor lymphocytes, called CD4+CD25+ T regulatory cells (T regs) that block the development of anti-tumor immunity, are made. 3) Determine if myeloid suppressor cells (MSC), which inhibit immunity by blocking the development of other cells that are essential for effective anti-tumor immunity, are present. Study Design: Primary mammary gland tumors will be surgically removed from mice with primary and metastatic mammary carcinoma (4T1tumor). At different time points thereafter as metastatic disease progresses, individual mice will be tested for tolerance (Aim 1), MSC (Aim 2), or T regs. Metastatic disease will be quantified and compared to immune responsiveness. Potential Outcomes and Benefits: Patients with metastatic breast cancer are potential candidates for novel immunotherapies. These studies will provide valuable information on the effects of metastatic disease on an individual’s ability to respond to immunotherapy. This information is essential for predicting if patients will be responsive to immunotherapy, and for identifying a potential therapeutic “window.”