Primary tumor-induced immunity eradicates disseminated tumor cells in syngeneic mouse model

Raziye Piranlioglu,Esteban Celis,Daniela Marasco,John K Cowell,Mustafa Guzel,Roni J Bollag,Eunmi Lee,Hasan Korkaya,Alicia H Vinyard,Ahmed Chadli,Muthushamy Thangaraju,Khaled A Hassan,Ali S Arbab,Maria Ouzounova,Max S Wicha

doi:10.1038/s41467-019-09015-1

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 EMT6-tumor 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 G-CSF 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.

Highlights

Clinically apparent metastasis is associated with late stages of cancer development, micro-metastatic dissemination may be an early event
We provide evidence that primary tumor-induced immune response clears disseminated tumor cells (DTC) following the complete resection of primary tumors in syngeneic mouse model
Our findings support the concept that DTCs may be eliminated by the innate and adaptive immune surveillance[3,9]

Summary

Introduction

Clinically apparent metastasis is associated with late stages of cancer development, micro-metastatic dissemination may be an early event. In line with the concept, we recently demonstrated that infiltration of a granulocytic subset of myeloidderived suppressor cells (gMDSC) in lungs creates such premetastatic niches in 4T1 tumor-bearing mice[24] In this model, gMDSCs suppress antitumor immunity, but they promote the epithelial phenotype of cancer stem cells (CSC), which were shown to be proliferative[25]. In line with the immunesurveillance concept, we show that EMT6 tumors in syngeneic BALB/c mice induce antitumor immunity, resulting in clearance of DTCs in distant organs. This clearance was mediated by cytotoxic T lymphocytes (CTL), but not by natural killer (NK) cells, as previously reported[26,27]. Mice are cured and free of DTCs when primary tumors are completely resected, while mice with residual tumors following surgery show enhanced growth of recurrent primary tumors and concomitant growth of DTCs at the metastatic site

Methods

Results

Conclusion