Expansion of CCR8+ Inflammatory Myeloid Cells in Cancer Patients with Urothelial and Renal Carcinomas

Abstract

Purpose Chemokines are involved in cancer-related inflammation and malignant progression. In this study we evaluated expression of CCR8 and its natural cognate ligand CCL1 in patients with urothelial carcinomas of bladder and renal cell carcinomas. Experimental Design We examined CCR8 expression in peripheral blood and tumor tissues from patients with bladder and renal carcinomas. CCR8-positive myeloid cells were isolated from cancer tissues with magnetic beads and tested in vitro for cytokine production and ability to modulate T cell function. Results We demonstrate that monocytic and granulocytic myeloid cell subsets in peripheral blood of cancer patients with urothelial and renal carcinomas display increased expression of chemokine receptor CCR8. Up-regulated expression of CCR8 is also detected within human cancer tissues and primarily limited to tumor-associated macrophages (TAMs). When isolated, CD11b+CCR8+ cell subset produces the highest levels of pro-inflammatory and pro-angiogenic factors among intratumoral CD11b myeloid cells. Tumor-infiltrating CD11b+CCR8+ cells selectively display activated Stat3 and are capable of inducing FoxP3 expression in autologous T lymphocytes. Primary human tumors produce substantial amounts of the natural CCR8 ligand CCL1. Conclusions This study provides the first evidence that CCR8+ myeloid cell subset is expanded in cancer patients. Elevated secretion of CCL1 by tumors, increased presence of CCR8+ myeloid cells in peripheral blood and cancer tissues indicate that CCL1/CCR8 axis is a component of cancer-related inflammation and may contribute to immune evasion. Obtained results also implicate that blockade of CCR8 signals may provide an attractive strategy for therapeutic intervention in human urothelial and renal cancers.

Glycosylated extracellular vesicles released by glioblastoma cells are decorated by CCL18 allowing for cellular uptake via chemokine receptor CCR8

“…The CCR8 axis has been found to be activated in urothelial and renal carcinomas resulting in immune response impairment, and it is responsible for apoptosis inhibition in lymphoma [53,54]. Furthermore, CCR8 function in melanoma cells is essential for the entry of metastatic cells into lymph nodes [55].…”

Tumor Associated Macrophages in Kidney Cancer

“…Though unexpected, another specific property of TAMs in RCC is expression of CCR8 associated with higher activity of Stat3-mediated signaling, which is rather typical for inflammatory phenotype. These cells are considered to be capable of stimulating FoxP3 expression in T-cells and have proangiogenic activity [33]. …”

An optimized disaggregation method for human lung tumors that preserves the phenotype and function of the immune cells

“…Ideally, this process, termed "disaggregation," should be gentle enough to maximize viability and minimize biologic alterations, yet robust enough to optimize cell yield and ensure that the final product accurately represents the in vivo cellular populations [1,2]. Currently, no standardized techniques exist for the disaggregation of human tumor tissue Traditionally, efforts have used matrix-degrading enzymes [2][3][4][5][6][7][8][9][10] and mechanical manipulation [3,4,11,12] to disrupt cellular attachments, break down the ECM, and liberate individual cells [13]. Methods of mechanical disaggregation (mincing, slicing, homogenizing) are rapid and simple, but they tend to generate suspensions characterized by high cellular damage and low cell recovery [3,4,6].…”