Myeloid‐derived suppressor cells (MDSCs) and tumor‐associated macrophages (TAMs) produce CCL22 which selectively recruits regulatory T‐cells (Tregs) to the tumor microenvironment

Abstract

Tumor‐induced immune suppression involves the accumulation of immune suppressive infiltrates in the microenvironment. We demonstrated an increased number of Tregs in Lewis Lung Carcinoma (LLC). High levels of CCR4 on Tregs lead us to hypothesize that CCR4‐chemokines are secreted by LLC and selectively recruit Tregs. ELISA shows a large increase in CCL22 secretion by LLC bearing tissue. Lack of CCL22 in primary cultures suggests that CCL22 is NOT produced by the tumor, but rather by some other component of the microenvironment. Migration assays showed that normal, and to a greater extent, LLC‐bearing tissue selectively recruits Tregs. Neutralization of CCL22 significantly reduced the selective Treg migration. Fractionated normal and LLC bearing tissue shows that while NK, CD31+, and CD11c+ cells all produce CCL22, only the CD11b+ population secretes higher levels in LLC bearing tissue. This is magnified by the increased number of CD11b+ cells found in LLC bearing tissue. Of the CD11b+ cells, two populations emerge. One population is absent in normal lung tissue and expresses F4/80, suggesting that these are TAMs. The other population expresses Gr‐1, which is consistent with MDSCs. Together, our data suggests that other immune suppressive phenotypes such as TAMS and MDSCs play an active role in Treg recruitment to the microenvironment through the production of CCL22.Supported by the Dept. of Veteran's Affairs & NIH