Stromal CCR6 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages.
Interactions between the inflammatory chemokine CCL20 and its receptor CCR6 have been implicated in promoting colon cancer; however, the mechanisms behind this effect are poorly understood. We have previously demonstrated that deficiency of CCR6 is associated with decreased tumor macrophage accumulation in a model of sporadic intestinal tumorigenesis. In this study, we aimed to determine the role of stromal CCR6 expression in a murine syngeneic transplantable colon cancer model. We show that deficiency of host CCR6 is associated with decreased growth of syngeneic CCR6-expressing colon cancers. Colon cancers adoptively transplanted into CCR6-deficient mice have decreased tumor-associated macrophages without alterations in the number of monocytes in blood or bone marrow. CCL20, the unique ligand for CCR6, promotes migration of monocytes in vitro and promotes accumulation of macrophages in vivo. Depletion of tumor-associated macrophages decreases the growth of tumors in the transplantable tumor model. Macrophages infiltrating the colon cancers in this model secrete the inflammatory mediators CCL2, IL-1α, IL-6 and TNFα. Ccl2, Il1α and Il6 are consequently downregulated in tumors from CCR6-deficient mice. CCL2, IL-1α and IL-6 also promote proliferation of colon cancer cells, linking the decreased macrophage migration into tumors mediated by CCL20-CCR6 interactions to the delay in tumor growth in CCR6-deficient hosts. The relevance of these findings in human colon cancer is demonstrated through correlation of CCR6 expression with that of the macrophage marker CD163 as well as that of CCL2, IL1α and TNFα. Our findings support the exploration of targeting the CCL20-CCR6 pathway for the treatment of colon cancer.
Research Service, VA Boston Healthcare System, West Roxbury, MA, USA; Harvard Medical School, Boston, MA, USA.
Bisweswar
B
Nandi
Research Service, VA Boston Healthcare System, West Roxbury, MA, USA; Harvard Medical School, Boston, MA, USA.
Mia
M
Shapiro
Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA.
Mehmet K
MK
Samur
Research Service, VA Boston Healthcare System , West Roxbury, MA, USA.
Christine
C
Pai
Harvard Medical School, Boston, MA, USA; Medicine Service, VA Boston Healthcare System, West Roxbury, MA, USA; Brigham and Women's Hospital, Boston, MA, USA.
Natasha Y
NY
Frank
Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA.
Charles
C
Yoon
Research Service, VA Boston Healthcare System, West Roxbury, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA.
Rao H
RH
Prabhala
Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Medicine Service, VA Boston Healthcare System, West Roxbury, MA, USA.
Nikhil C
NC
Munshi
Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA; Surgery Service, VA Boston Healthcare System, West Roxbury, MA, USA.
Jason S
JS
Gold
CCR6; chemokine CCL20; colorectal cancer; macrophages; mice; receptors