Targeted Repolarization of Tumor‐Associated Macrophages via Imidazoquinoline‐Linked Nanobodies

Bolli, Evangelia; Scherger, Maximilian; Arnouk, Sana M.; Antunes, Ana Rita Pombo; Straßburger, David; Urschbach, Moritz; Stickdorn, Judith; Vlaminck, Karen De; Movahedi, Kiavash; Räder, Hans Joachim; Hernot, Sophie; Besenius, Pol; Ginderachter, Jo A. Van; Nuhn, Lutz

doi:10.1002/advs.202004574

Cited by 45 publications

(36 citation statements)

References 67 publications

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“…The anti-MMR Nb-IMDQ conjugates resulted in efficient drug delivery to TAMs high in MMR expression and significantly decreased tumor growth, aligned with an increased antitumor T-cell response by repolarizing TAMs toward a proinflammatory phenotype (Fig. 6 ) [ 147 ]. TAMs were found to be required for antibody-dependent cell phagocytosis, which has been considered a key mechanism for antibody cancer therapy.…”

Section: Main Textmentioning

confidence: 99%

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Tumor-associated macrophages in cancer: recent advancements in cancer nanoimmunotherapies

Kumari

Choi

2022

J Exp Clin Cancer Res

144

106

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Cancer immunotherapy has emerged as a novel cancer treatment, although recent immunotherapy trials have produced suboptimal outcomes, with durable responses seen only in a small number of patients. The tumor microenvironment (TME) has been shown to be responsible for tumor immune escape and therapy failure. The vital component of the TME is tumor-associated macrophages (TAMs), which are usually associated with poor prognosis and drug resistance, including immunotherapies, and have emerged as promising targets for cancer immunotherapy. Recently, nanoparticles, because of their unique physicochemical characteristics, have emerged as crucial translational moieties in tackling tumor-promoting TAMs that amplify immune responses and sensitize tumors to immunotherapies in a safe and effective manner. In this review, we mainly described the current potential nanomaterial-based therapeutic strategies that target TAMs, including restricting TAMs survival, inhibiting TAMs recruitment to tumors and functionally repolarizing tumor-supportive TAMs to antitumor type. The current understanding of the origin and polarization of TAMs, their crucial role in cancer progression and prognostic significance was also discussed in this review. We also highlighted the recent evolution of chimeric antigen receptor (CAR)-macrophage cell therapy.

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Section: Main Textmentioning

confidence: 99%

“…G Percentage of effector (CD44 + CD62L−) cells within CD4+ T cells and Gzmb+ cells within CD8+ T cells is shown as mean ± SEM. p ≤ 0.05; **: p ≤ 0.01 [ 147 ] …”

Section: Main Textmentioning

confidence: 99%

Tumor-associated macrophages in cancer: recent advancements in cancer nanoimmunotherapies

Kumari

Choi

2022

J Exp Clin Cancer Res

144

106

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“…To confirm the IHC results on infiltrated macrophages, we performed flow cytometry analysis of size‐matched tumors (Figure S2D , Supporting Information). We adapted a protocol described by Bolli et al., [ 31 ] and defined macrophages by their CD45 + CD11b + Ly6C lo‐int Ly6G − SiglecF − F4/80 hi phenotype (Figure S2F , Supporting Information). As shown in Figure 2D, a profound reduction of total macrophages was obtained in PYK2 KO tumors as well as significantly less Ly6C hi monocytes (Figure 2E ), which may represent a subset of myeloid‐derived suppressor cells.…”

Section: Resultsmentioning

confidence: 99%

Mouse Modeling Dissecting Macrophage–Breast Cancer Communication Uncovered Roles of PYK2 in Macrophage Recruitment and Breast Tumorigenesis

et al. 2022

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Macrophage infiltration in mammary tumors is associated with enhanced tumor progression, metastasis, and poor clinical outcome, and considered as target for therapeutic intervention. By using different genetic mouse models, the authors show that ablation of the tyrosine kinase PYK2, either in breast cancer cells, only in the tumor microenvironment, or in both, markedly reduces the number of infiltrating tumor macrophages and concomitantly inhibits tumor angiogenesis and tumor growth. Strikingly, PYK2 ablation only in macrophages is sufficient to induce similar effects. These phenotypic changes are associated with reduced monocyte recruitment and a substantial decrease in tumor‐associated macrophages (TAMs). Mechanistically, the authors show that PYK2 mediates mutual communication between breast cancer cells and macrophages through critical effects on key receptor signaling. Specifically, PYK2 ablation inhibits Notch1 signaling and consequently reduces CCL2 secretion by breast cancer cells, and concurrently reduces the levels of CCR2, CXCR4, IL‐4Rα, and Stat6 activation in macrophages. These bidirectional effects modulate monocyte recruitment, macrophage polarization, and tumor angiogenesis. The expression of PYK2 is correlated with infiltrated macrophages in breast cancer patients, and its effects on macrophage infiltration and pro‐tumorigenic phenotype suggest that PYK2 targeting can be utilized as an effective strategy to modulate TAMs and possibly sensitize breast cancer to immunotherapy.

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“…The TAMs can remain in multiple states of polarization. Still, a large number of research teams use a simpler model in which microglia and macrophages exist in “resting” M0, tumor-promoting and immunosuppressive M2, and anti-tumor or proinflammatory M1 states, with most literature evidence supporting the view that the M2-type constitutes the majority of the TAMs [ 37 , 38 , 39 , 40 , 41 , 42 ]. In fact, all these teams maintain that cytokines secreted by the tumor cells support the M2 state, and TAMs in the M2 state secrete factors that promote tumor progression and metastasis.…”

Section: Proposed Mechanism Of M2→m1 Repolarization Of Tams Recruitment Of Macrophages and Nk Cells And Tumor Eliminationmentioning

confidence: 99%

A New Perspective on Cancer Therapy: Changing the Treaded Path?

Baidoo

Mukherjee

Kashfi

2021

IJMS

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During the last decade, we have persistently addressed the question, “how can the innate immune system be used as a therapeutic tool to eliminate cancer?” A cancerous tumor harbors innate immune cells such as macrophages, which are held in the tumor-promoting M2 state by tumor-cell-released cytokines. We have discovered that these tumor-associated macrophages (TAM) are repolarized into the nitric oxide (NO)-generating tumoricidal M1 state by the dietary agent curcumin (CC), which also causes recruitment of activated natural killer (NK) cells and cytotoxic T (Tc) cells into the tumor, thereby eliminating cancer cells as well as cancer stem cells. Indications are that this process may be NO-dependent. Intriguingly, the maximum blood concentration of CC in mice never exceeds nanomolar levels. Thus, our results submit that even low, transient levels of curcumin in vivo are enough to cause repolarization of the TAM and recruitment NK cells as well as Tc cells to eliminate the tumor. We have observed this phenomenon in two cancer models, glioblastoma and cervical cancer. Therefore, this approach may yield a general strategy to fight cancer. Our mechanistic studies have so far implicated induction of STAT-1 in this M2→M1 switch, but further studies are needed to understand the involvement of other factors such as the lipid metabolites resolvins in the CC-evoked anticancer pathways.

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Targeted Repolarization of Tumor‐Associated Macrophages via Imidazoquinoline‐Linked Nanobodies

Cited by 45 publications

References 67 publications

Tumor-associated macrophages in cancer: recent advancements in cancer nanoimmunotherapies

Tumor-associated macrophages in cancer: recent advancements in cancer nanoimmunotherapies

Mouse Modeling Dissecting Macrophage–Breast Cancer Communication Uncovered Roles of PYK2 in Macrophage Recruitment and Breast Tumorigenesis

A New Perspective on Cancer Therapy: Changing the Treaded Path?

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