Primary Tumor-Induced Immunity Eradicates Disseminated Tumor Cells in Syngeneic Mouse Model

Raziye Piranlioglu, EunMi Lee, Maria Ouzounova, Roni J. Bollag, Alicia H. Vinyard1, Ali S. Arbab1, Daniela Marasco, <u>Mustafa Guzel,</u> John K. Cowell, Muthushamy Thangaraju1, Ahmed Chadli, Khaled A. Hassan, Max S. Wicha, Esteban Celis & Hasan Korkaya

Abstract

Although clinically apparent metastasis is associated with late stages of cancer development, micro-metastatic dissemination may be an early event. However, the fate of these early disseminated tumor cells (DTC) remains elusive. We show that despite their capacity to disseminate into secondary organs, 4T1 tumor models develop overt metastasis while EMT6tumor bearing mice clear DTCs shed from primary tumors as well as those introduced by intravenous (IV) injection. Following the surgical resection of primary EMT6 tumors, mice do not develop detectable metastasis and reject IV-injected tumor cells. In contrast, these cells readily grow and metastasize in immuno-deficient athymic or Rag2−/− mice, an effect mimicked by CD8+ T-cell depletion in immunocompetent mice. Furthermore, recombinant GCSF or adoptive transfer of granulocytic-MDSCs isolated from 4T1 tumor-bearing mice, induce metastasis by suppressing CD8+ T-cells in EMT6-primed mice. Our studies support the concept of immune surveillance providing molecular insights into the immune mechanisms during tumor progression.

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