Abstract
Macrophage-targeting therapies have become attractive strategies for immunotherapy. Deficiency of MARCO significantly inhibits tumor progression and metastasis in murine models of pancreatic cancer. However, the role of MARCO in patients with pancreatic cancer remains unclear. In the present study, we analyzed tumor-associated macrophage (TAM)-related changes using the Cancer Genome Atlas database. We observed a significant enrichment of M2 macrophages in pancreatic cancer tissues. We found that several pro-tumor markers are increased in cancer tissues, including CD163, CD206, SIRPα, LILRB1, SIGLEC10, AXL, MERTK, and MARCO. Crucially, MARCO is highly or exclusively expressed in pancreatic cancer across many types of solid tumors, suggesting its significant role in pancreatic cancer. Next, we investigated the expression of MARCO in relation to the macrophage marker CD163 in a treatment-naïve pancreatic cancer cohort after surgery (n = 65). MARCO and CD163 were analyzed using immunohistochemistry. We observed increased expression of CD163 and MARCO in pancreatic cancer tissues compared with paracancerous tissues. Furthermore, we observed a large variation in CD163 and MARCO expression in pancreatic cancer tissues among cases, suggesting the heterogeneous expression of these two markers among patients. Correlation to clinical data indicated a strong trend toward worse survival for patients with high CD163 and MARCO macrophage infiltration. Moreover, high CD163 and MARCO expression negatively affected the disease-free survival and overall survival rates of patients with pancreatic cancer. Univariate and multivariate analysis revealed that CD163 and MARCO expression was an independent indicator of pancreatic cancer prognosis. In conclusion, high CD163 and MARCO expression in cancer tissues is a negative prognostic marker for pancreatic cancer after surgery. Furthermore, anti-MARCO may be a novel therapy that is worth studying in depth.
Highlights
Pancreatic cancer remains a highly lethal malignancy and is expected to be the second leading cause of cancer death in the United States within the 20 to 30 years [1]
Research advances in PD-1/PD-L1 immune negative regulatory signaling pathways have driven tremendous advances in cancer immunotherapy
Clinical studies have demonstrated that only 25-30% of tumors suppress the immune response through the PD-1/PD-L1 pathway, whereas others escape the immune response through a different molecular pathway or mechanism [34]
Summary
Pancreatic cancer remains a highly lethal malignancy and is expected to be the second leading cause of cancer death in the United States within the 20 to 30 years [1]. As research has progressed, many immune escape mechanisms have been reported, including T cells, tumor-associated macrophages (TAMs), myeloid-derived suppression cells (MDSCs), and natural killer (NK) cells [7,8,9,10,11] Among these immune cells, TAMs constitute the vast majority in the tumor microenvironment, which indicates the possibility that macrophage-targeting therapies are novel and attractive strategies for cancer treatment [12]. Other preclinical trials targeting the macrophage “don’t eat me” signal have yielded impressive results through the promotion of tumor cell phagocytosis by macrophages, such as those involving the inhibition of the MHC-I-LILRB1 axis, inhibition of the CD24SIGLEC-10 axis, and CAR-M cellular immunotherapy [15,16,17] Despite these exciting findings, the role of macrophages in pancreatic cancer still needs to be fully uncovered
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