Selective targeting of tumor associated macrophages in different tumor models (original) (raw)
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Oncotarget, 2017
Cancer research in recent decades has highlighted the potential influence of the tumor microenvironment on the progression and metastasis of most known cancer types. Within the established microenvironment, tumor-associated macrophages (TAMs) are one of the most abundant and crucial non-neoplastic cell types. The polarization of macrophages into tumor-suppressive M1 or tumor-promoting M2 types is a fundamental event in the establishment of the tumor microenvironment. Although ample evidence indicates that TAMs are primarily M2 polarized, the mechanisms responsible for the regulation and maintenance of M1 and M2 polarization imbalance remain unclear. The manipulation of this critical axis through three main approaches may provide new strategies for cancer therapy - (I) specific interference with M2-like TAM survival or inhibiting their signaling cascades, (II) repression of macrophage recruitment to tumors, and (III) repolarization of tumor-promoting M2-like TAMs to a tumoricidal M1-...
European Journal of Cancer, 2006
Tumour-associated macrophages (TAM) represent the major inflammatory component of the stroma of many tumours, and can affect different aspects of the neoplastic tissue. Many observations indicate that TAM express several M2-associated pro-tumoural functions, including promotion of angiogenesis, matrix remodelling and suppression of adaptive immunity. The pro-tumoural role of TAM in cancer is further supported by clinical studies that found a correlation between the high macrophage content of tumours and poor patient prognosis. Evidence is presented here supporting the view that TAM represent a unique and distinct M2-skewed myeloid population and are a potential target for anti-cancer therapy.
METASTATIC CANCER Macrophages Polarization and Tumor Immunity in Metastatic Cancer : A Review
2021
Objective: Tumour microenvironment plays an important role in the progression of cancer. This review focussed on current understanding on M1-M2 macrophage polarisation and the possible therapeutic intervention against metastatic cancer. Discussion: Macrophages exhibit a variety of responses according to varying stimuli, and express different functions depending upon the microenvironment surrounding them. Macrophages can be activated by a variety of stimuli and polarized to functionally different phenotypes. Two distinct subsets of macrophages have been proposed; classically activated (M1) macrophages and alternatively activated (M2) macrophages. M1 macrophages express a series of pro-inflammatory cytokines, chemokines, and effector molecules, such as IL-6, IL-12, IL-23, TNF-α, iNOS and MHCI/II. In contrast, M2 macrophages express a wide array of anti-inflammatory molecules, such as IL-10, TGF-β, and arginase1. Tumour associated macrophages (TAM) of M2 type secrete many cytokines, ch...
Macrophage polarity in cancer: A review
Macrophages are the most abundant cells within the tumor stroma displaying noticeable plasticity, which allows them to perform several functions within the tumor microenvironment. Tumor-associated macrophages commonly refer to an alternative M2 phenotype, exhibiting anti-inflammatory and pro-tumoral effects. M2 cells are highly versatile and multi-tasking cells that directly influence multiple steps in tumor development, including cancer cell survival, proliferation, stemness, and invasiveness along with angiogenesis and immunosuppression. M2 cells perform these functions through critical interactions with cells related to tumor progression, including Th2 cells, cancer-associated fibroblasts, cancer cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells. M2 cells also have negative cross-talks with tumor suppressor cells, including cytotoxic T cells and natural killer cells. Programed death-1 (PD-1) is one of the key receptors expressed in M2 cells that, upon interaction with its ligand PD-L1, plays cardinal roles for induction of immune evasion in cancer cells. In addition, M2 cells can neutralize the effects of the pro-inflammatory and anti-tumor M1 phenotype. Classically activated M1 cells express high levels of major histocompatibility complex molecules, and the cells are strong killers of cancer cells. Therefore, orchestrating M2 reprogramming toward an M1 phenotype would offer a promising approach for reversing the fate of tumor and promoting cancer regression. Macrophage switching toward an anti-inflammatory M1 phenotype could be used as an adjuvant with other approaches, including radiotherapy and immune checkpoint blockades, such as anti-PD-L1/PD-1 strategies.
Frontiers in Oncology, 2020
Tumor microenvironment (TME) is composed of tumor cells and surrounding non-tumor stromal cells, mainly including tumor associated macrophages (TAMs), endothelial cells, and carcinoma-associated fibroblasts (CAFs). The TAMs are the major components of non-tumor stromal cells, and play an important role in promoting the occurrence and development of tumors. Macrophages originate from bone marrow hematopoietic stem cells and embryonic yolk sacs. There is close crosstalk between TAMs and tumor cells. With the occurrence of tumors, tumor cells secrete various chemokines to recruit monocytes to infiltrate tumor tissues and further promote their M2-type polarization. Importantly, M2-like TAMs can in turn accelerate tumor growth, promote tumor cell invasion and metastasis, and inhibit immune killing to promote tumor progression. Therefore, targeting TAMs in tumor tissues has become one of the principal strategies in current tumor immunotherapy. Current treatment strategies focus on reducing macrophage infiltration in tumor tissues and reprogramming TAMs to M1like to kill tumors. Although these treatments have had some success, their effects are still limited. This paper mainly summarized the recruitment and polarization of macrophages by tumors, the support of TAMs for the growth of tumors, and the research progress of TAMs targeting tumors, to provide new treatment strategies for tumor immunotherapy.
OncoImmunology, 2021
M2-like tumor-associated macrophages promote tumor progression by establishing an immunosuppressive tumor microenvironment. The phenotype and activity of immunosuppressive macrophages are related to their mitochondrial metabolism. Thus, we studied if drugs targeting mitochondrial metabolic pathways can repolarize macrophages from M2 into an M1-like phenotype or can prevent M0-to-M2 polarization. The drugs selected are clinically approved or in clinical trials and target M2-specific metabolic pathways: fatty acid oxidation (Perhexiline and Trimetazidine), glutaminolysis (CB-839), PPAR activation (HX531), and mitochondrial electron transport chain (VLX-600). Murine bone marrow-derived macrophages were either polarized to M2 using IL-4 in the presence of the drugs or polarized first into M2 and then treated with the drugs in presence of IFN-γ for re-polarization. Targeting both fatty acid oxidation with Perhexiline or the electron transport chain with VLX-600 in the presence of IFN-γ, impaired mitochondrial basal, and maximal respiration and resulted in M2 to M1-like re-polarization (increased iNOS expression, NO production, IL-23, IL-27, and TNF-α secretion), similar to LPS+IFN-γ re-polarization. Moreover, drug-induced macrophage re-polarization resulted in a strong tumor-cytotoxic activity. Furthermore, the polarization of M0-to M2-like macrophages was impaired by CB-839, Trimetazidine, HX531, and Perhexiline, while Hx531 and Perhexiline also reduced MCP-1 secretion. Our results show that by targeting cell metabolism, macrophages could be re-polarized from M2-into an anti-tumoral M1-like phenotype and that M0-to-M2 polarization could be prevented. Overall, this study provides rational for the use of clinically applicable drugs to change an immunosuppressive tumor environment into a proinflammatory tumor environment that could support cancer immunotherapies.
Serum Stability and Affinity Optimization of an M2 Macrophage-Targeting Peptide (M2pep)
Theranostics, 2016
Tumor associated macrophages (TAMs) are a major stromal component of the tumor microenvironment in several cancers. TAMs are a potential target for adjuvant cancer therapies due to their established roles in promoting proliferation of cancer cells, angiogenesis, and metastasis. We previously discovered an M2 macrophage-targeting peptide (M2pep) which was successfully used to target and deliver a pro-apoptotic KLA peptide to M2-like TAMs in a CT-26 colon carcinoma model. However, the effectiveness of in vivo TAM-targeting using M2pep is limited by its poor serum stability and low binding affinity. In this study, we synthesized M2pep derivatives with the goals of increasing serum stability and binding affinity. Serum stability evaluation of M2pepBiotin confirmed its rapid degradation attributed to exolytic cleavage from the N-terminus and endolytic cleavages at the W10/W11 and S16/K17 sites. N-terminal acetylation of M2pepBiotin protected the peptide against the exolytic degradation while W10w and K(17,18,19)k substitutions were able to effectively protect endolytic degradation at their respective cleavage sites. However, no tested amino acid changes at the W10 position resulted in both protease resistance at that site and retention of binding activity. Therefore, cyclization of M2pep was investigated. Cyclized M2pep better resisted serum degradation without compromising binding activity to M2 macrophages. During the serum stability optimization process, we also discovered that K9R and W10Y substitutions significantly enhanced binding affinity of M2pep. In an in vitro binding study of different M2pep analogs pre-incubated in mouse serum, cyclic M2pep with K9R and W10Y modifications (cyclic M2pep(RY)) retained the highest binding activity to M2 macrophages over time due to its improved serum stability. Finally, we evaluated the in vivo accumulation of sulfo-Cy5-labeled M2pep and cyclic M2pep(RY) in both the CT-26 and 4T1 breast carcinoma models. Cyclic M2pep(RY) outperformed M2pep in both tumor localization and selective accumulation in M2-like TAMs. In conclusion, we report cyclic M2pep(RY) as our lead M2pep analog with improved serum stability and M2 macrophage-binding activity. Its enhanced utility as an in vivo M2-like-TAM-targeting agent was demonstrated in two tumor models, and is expected to be applicable for other tumor models or in models of M2 macrophage-related diseases.