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Targeting the Immune System's Natural Response to Cell Death to Improve Therapeutic Response in Breast Cancers

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Annual rept. 1 Jun 2013-31 May 2014

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We have proposed experiments to test the hypothesis that MerTK-mediated efferocytosis by tumor associated macrophages TAMs is a major limitation to effective therapeutic responses, because efferocytosis of dying tumor cells drives production of wound-healingTh2-like cytokines, limits anti-tumor immunity, and promotes tumor growth. Scope Two Aims were proposed to test this hypothesis. The goal of Aim 1 was to determine if MerTK-directed efferocytosis modulates cytokine expression, leukocyte infiltration, and growth of mouse mammary tumors, specifically testing the hypothesis that loss of MerTK would impair efferocytosis of dying tumor cells by TAMs, thus limiting production of Th2WH cytokines in the tumor microenvironment TME, resulting in decreased tumor growth and metastasis. The goal of Aim 2 was to measure the impact of MerTK-directed efferocytosis on tumor re-emergence in therapeutically treated breast cancers, specifically testing the hypothesis that loss of MerTK-directed efferocytosis in the TME will limit Th2WH cytokines, thereby preventing immune tolerance and tumor regrowth. Major Findings and Up-to-Date Report of Progress As indicated in the Statement of Work, the major tasks for year 1 involve mouse breeding strategies to generate the genetic model with which we may test the role of efferocytosis in spontaneously arising mammary tumors. This has been accomplished according to schedule, such that we are now observing mice daily to assess tumor formation.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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