CCL28 Downregulation Attenuates Pancreatic Cancer Progression Through Tumor Cell-Intrinsic and -Extrinsic Mechanisms

Abstract

C-C motif chemokine ligand 28 (CCL28) has been reported to be pro-tumoral in several cancer types. However, the role of CCL28 in pancreatic ductal adenocarcinoma (PDAC) progression remains unclear. CCL28 mRNA expression in tumors from PDAC patients was found to be elevated as compared to normal pancreas. CCL28 expression was also negatively correlated with overall survival (OS) in pancreatic cancer patients. Our in vitro experiments showed that CCL28 knockdown impairs the proliferation of mouse pancreatic cancer cell line PAN02. Moreover, in both immunocompetent syngeneic mice and immunodeficient NOD-SCID mice, CCL28 deficiency significantly attenuated the growth of subcutaneous PAN02 tumors. In syngeneic mouse model, CCL28 downregulation remodeled the pancreatic tumor microenvironment by suppressing the infiltration of both regulatory T (Treg) cells, myeloid-derived suppressor cells, and activated pancreatic stellate cells, and upregulating the expression of lymphocyte cytotoxic proteins including perforin and granzyme B. In conclusion, our work demonstrates that CCL28 is a potential target for pancreatic cancer treatment and CCL28 blockade could inhibit tumor growth through both tumor-cell-intrinsic and extrinsic mechanisms.

RBPJ Deficiency Sensitizes Pancreatic Acinar Cells to KRAS-Mediated Pancreatic Intraepithelial Neoplasia Initiation

“…CXCL2 recruits neutrophils in the early stage of tissue damage. 52 Interestingly, CCL28, CXCL14, and CCL20 are known to be elevated in the PDAC patients 53 , 54 , 55 and among those, CCL28 and CXCL14 correlate with a poor clinical outcome. 53 , 54 In contrast, CCL7 was considered to possess antitumoral effect in pancreatic cancer by enhancing natural killer cell infiltration.…”

“…52 Interestingly, CCL28, CXCL14, and CCL20 are known to be elevated in the PDAC patients 53 , 54 , 55 and among those, CCL28 and CXCL14 correlate with a poor clinical outcome. 53 , 54 In contrast, CCL7 was considered to possess antitumoral effect in pancreatic cancer by enhancing natural killer cell infiltration. 56 Moreover, cytokines like IL-2, IL-6, IL-17a, and IL-11 were higher expressed in iKCR mice.…”

Single-Cell Sequencing Combined with Transcriptome Sequencing Constructs a Predictive Model of Key Genes in Multiple Sclerosis and Explores Molecular Mechanisms Related to Cellular Communication

“… 75 Blockade of CCL28 was reported to inhibit tumor growth in pancreatic cancer through tumor cell-intrinsic and extrinsic mechanisms. 76 CXCL14 plays important roles in the infiltration of immune cells involved in cancer, the immune response, and epithelial cell proliferation and migration. It may play opposite roles in different cancers but is still a promising target for cancer immunotherapy.…”

NKT cells contribute to alleviating lung metastasis in adenoid cystic carcinoma

“…CCL28 was reported as a chemokine closely associated with the metastasis of gastric, breast, and pancreatic cancers. [41][42][43] CCL28 can chemoattract CD8 and CD4 T cells in the blood into tissues through receptors CCR10 and CCR3 33 and could underlie the inflammatory pattern. The association between NKT cells and SACC lung metastases deserves further investigation.…”

“…Unlike in primary tissues, inflamed metastatic lung tissue, CCL28 was the only overexpressed chemokine. CCL28 was reported as a chemokine closely associated with the metastasis of gastric, breast, and pancreatic cancers 41–43 . CCL28 can chemoattract CD8 and CD4 T cells in the blood into tissues through receptors CCR10 and CCR3 33 and could underlie the inflammatory pattern.…”