The CD151‐midkine pathway regulates the immune microenvironment in inflammatory breast cancer

Abstract

The immune microenvironment in inflammatory breast cancer (IBC) is poorly characterised, and molecular and cellular pathways that control accumulation of various immune cells in IBC tissues remain largely unknown. Here, we discovered a novel pathway linking the expression of the tetraspanin protein CD151 in tumour cells with increased accumulation of macrophages in cancerous tissues. It is notable that elevated expression of CD151 and a higher number of tumourinfiltrating macrophages correlated with better patient responses to chemotherapy. Accordingly, CD151-expressing IBC xenografts were characterised by the increased infiltration of macrophages. In vitro migration experiments demonstrated that CD151 stimulates the chemoattractive potential of IBC cells for monocytes via mechanisms involving midkine (a heparin-binding growth factor), integrin α6β1, and production of extracellular vesicles (EVs). Profiling of chemokines secreted by IBC cells demonstrated that CD151 increases production of midkine. Purified midkine specifically stimulated migration of monocytes, but not other immune cells. Further experiments demonstrated that the chemoattractive potential of IBC-derived EVs is blocked by anti-midkine antibodies. These results demonstrate for the first time that changes in the expression of a tetraspanin protein by tumour cells can affect the formation of the immune microenvironment by modulating recruitment of effector cells to cancerous tissues. Therefore, a CD151-midkine pathway can be considered as a novel target for controlled changes of the immune landscape in IBC.

Combined exome and transcriptome sequencing of non-muscle-invasive bladder cancer: associations between genomic changes, expression subtypes, and clinical outcomes

“…In NMIBCs with ERBB2 amplification, the most upregulated gene detected was TLK2 (limma based p.adj value = 2.67 × 10e−02) (Additional file 1 : Table S8) which has been reported to suppress the innate immune system [ 53 ]. CD151 (a marker for T-cell activation [ 54 ] and/or macrophage infiltration [ 55 ]) was also downregulated ( p -value = 3.78 × 10e−5). The ConsensusTME immune score was lower in ERBB2 -amplified NMIBCs but was not statistically significant (Mann-Whitney p -value = 0.12).…”

The Context-Dependent Impact of Integrin-Associated CD151 and Other Tetraspanins on Cancer Development and Progression: A Class of Versatile Mediators of Cellular Function and Signaling, Tumorigenesis and Metastasis

“…These diverse functions highlight a key basis for the crucial role of CD151 across a wide spectrum of human cancer [ 1 , 3 ]. Additionally, the presence of CD151 in exosomes derived from tumors or their microenvironments suggests a new mechanism for its role in tumor relapse and drug resistance [ 41 , 48 , 54 ]. There is also evidence on the cell lineage- and oncogenic context-dependent roles of CD151 and other tetraspanins [ 28 , 29 , 48 , 50 , 71 , 93 , 166 ].…”

“…Interestingly, in breast cancer cells exhibiting a strong promoting role of CD151, receptor tyrosine kinases (RTKs) (e.g., EGFR, ErbB2, c-Met and Ron) or K-Ras are frequently activated because of gene amplification/overexpression or mutations (Figure 1) [1]. Part of the pro-metastatic role of CD151 may be linked to its regulation of tumor angiogenesis and microenvironments, as it supports function and integrity of vascular endothelial cells and infiltration of tumor-associated macrophages [25,28,48,74,75]. Consistent with these observations, CD151 deletion markedly decreases expression of several key myeloid cell-associated hallmark genes in mammary tumors, including CD36 and MMP2 [28].…”

“…Suppress inflammatory breast cancer through regulation of macrophage recruitment [ 48 ].…”

Progress for Immunotherapy in Inflammatory Breast Cancer and Emerging Barriers to Therapeutic Efficacy

“…This was recapitulated in patient-derived xenografts, where CD151 expression tumors displayed an increase in TAMs, mediated by increased expression of the monocyte chemoattractant midkine. The authors conclude that therapeutic inhibition of CD151/midkine signaling may offer a potential strategy to reshape the immune milieu of IBC tumors [ 45 ]. Hence, though the roles of TAMs in IBC are still emerging, it is clear that they serve an important role in shaping the IBC TME and warrant consideration when designing immune-based therapies.…”