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Cognate Interaction With CD4+ T Cells Instructs Tumor-Associated Macrophages to Acquire M1-Like Phenotype.

ABSTRACT: The immunosuppressive tumor microenvironment (TME) established by tumor cells, stromal cells and inhibitory immune cells counteracts the function of tumor reactive T cells. Tumor associated macrophages (TAMs) showing functional plasticity contribute to this process as so called M2-like macrophages can suppress the function of effector T cells and promote their differentiation into regulatory T cells (Tregs). Furthermore, tumor antigen specific CD4+ T effector cells can essentially sustain anti-tumoral immune responses as shown for various tumor entities, thus suggesting that cognate interaction between tumor antigen-specific CD4+ Th1 cells and TAMs might shift the intra-tumoral M1/M2 ratio toward M1. This study demonstrates repolarization of M2-like PECs upon MHC II-restricted interaction with tumor specific CD4+ Th1 cells in vitro as shown by extensive gene and protein expression analyses. Moreover, adoptive transfer of OVA-specific OT-II cells into C57BL/6 mice bearing OVA expressing IAb-/- tumors resulted in increased accumulation of M1-like TAMs with enhanced M1 associated gene and protein expression profiles. Thus, this paper highlights a so far underestimated function of the CD4+ Th1/TAM axis in re-conditioning the immunosuppressive tumor microenvironment.

SUBMITTER: Eisel D

PROVIDER: S-EPMC6395406 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Cognate Interaction With CD4<sup>+</sup> T Cells Instructs Tumor-Associated Macrophages to Acquire M1-Like Phenotype.

Eisel David D Das Krishna K Dickes Elke E König Rainer R Osen Wolfram W Eichmüller Stefan B SB

Frontiers in immunology 20190222

The immunosuppressive tumor microenvironment (TME) established by tumor cells, stromal cells and inhibitory immune cells counteracts the function of tumor reactive T cells. Tumor associated macrophages (TAMs) showing functional plasticity contribute to this process as so called M2-like macrophages can suppress the function of effector T cells and promote their differentiation into regulatory T cells (Tregs). Furthermore, tumor antigen specific CD4<sup>+</sup> T effector cells can essentially sus ...[more]

PMID: 30853959

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Project description:BackgroundTumor-associated macrophages (TAMs) have a leading position in the tumor microenvironment. Previously, we have demonstrated that M1-like TAMs activated by exosome-transferred THBS1 promote malignant migration in oral squamous cell carcinoma (OSCC). However, the functional roles and associated molecular mechanisms of the activated M1-like TAMs need to be further clarified in OSCC.MethodsConditioned Media (CM) were harvested from the exosome activated M1-like TAMs. We measured the malignant behaviors of OSCC under the treatment of CM from M1-like TAMs by performing colony forming assays, invasion assays, wound-healing assays, spheroid forming assays and in vivo xenograft experiments. The underlying mechanisms were investigated by RNA-seq, cytokines analysis, intracellular signaling pathway analysis, ChIP assays, bioinformatics analysis and validation.ResultsM1-like TAMs significantly promoted the epithelial-mesenchymal transition (EMT) process, and induced the cancer-stem like cells (CSCs) by upregulating the expression of MME and MMP14 in OSCC cells. Cytokine analysis revealed a shark increase of IL6 secretion from M1-like TAMs. Blocking IL6 in the CM from M1-like TAMs could significantly weaken its effects on the colony forming, invasion, migration, microsphere forming and xenograft forming abilities of OSCC cells. Cellular signaling assays indicated the activation of Jak/Stat3 pathway in the OSCC cells treated by the CM from M1-like TAMs. Blocking the activation of the Jak/Stat3 pathway could significantly weaken the effects of M1-like TAMs on the colony forming, invasion, migration, microsphere forming and xenograft forming abilities of OSCC cells. Further RNA-seq analysis and bioinformatics analysis revealed an increased expression of THBS1 in the OSCC cells treated by M1-like TAMs. Bioinformatics prediction and ChIP assays revealed the activation of Stat3 by CM from M1-like TAMs could directly promote the transcription of THBS1 in OSCC cells.ConclusionsWe proposed that M1-like TAMs could cascade a mesenchymal/stem-like phenotype of OSCC via the IL6/Stat3/THBS1 feedback loop. A better understanding on the functional roles and associated molecular mechanisms of M1-like TAMs might facilitate the development of novel therapies for supplementing the current treatment strategies for OSCC patients.

Project description:BackgroundTumor-associated macrophages (TAMs) are classified into two major phenotypes, M1 and M2. M1 TAMs suppress cancer progression, while M2 TAMs promote it. However, little is known regarding the role of TAMs in the development of ovarian cancer. Here, we investigated the relationship between TAM distribution patterns (density, microlocalization, and differentiation) and ovarian cancer histotypes, and we explored whether altered TAM distribution patterns influence long-term outcomes in ovarian cancer patients.MethodsA total of 112 ovarian cancer patients were enrolled in this study, and the subjects were divided into two groups according to their survival (< 5 years vs. ? 5 years). Immunohistochemistry and immunofluorescence were used to determine the density, microlocalization, and differentiation status of TAMs in ovarian cancer tissues for each histotype. Kaplan-Meier survival and multivariate Cox regression analyses were used to evaluate the prognostic significance of TAM-related parameters in ovarian cancer.ResultsTAMs most frequently infiltrated into the cancer tissue of the serous histotype, followed by mucinous, undifferentiated, endometrioid, and clear cell histotypes (p?=?0.049). The islet/stroma ratio of total TAMs varied among the cancer histotypes, with mucinous and undifferentiated cancers displaying the lowest and highest ratios, respectively (p?=?0.005). The intratumoral TAM density significantly increased with increasing cancer stage and grade (p?=?0.023 and 0.006, respectively). However, the overall M1/M2 TAM ratio decreased as the cancer stage increased (p?=?0.012). In addition, the intra-islet M1/M2 ratio inversely correlated with the residual site size (p?=?0.004). Among the TAM-related parameters, only the increased overall and intra-islet M1/M2 TAM ratios displayed prognostic significance in both the Kaplan-Meier survival and multivariate Cox regression analyses; however, the values of these two parameters did not differ significantly among the cancer histotypes.ConclusionsThe patients with increased overall or intra-islet M1/M2 TAM ratios presented with an improved 5-year prognosis. Nevertheless, the TAM distribution patterns did not influence the overall outcomes of different ovarian cancer histotypes.

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Cognate Interaction With CD4+ T Cells Instructs Tumor-Associated Macrophages to Acquire M1-Like Phenotype.

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Cognate Interaction With CD4<sup>+</sup> T Cells Instructs Tumor-Associated Macrophages to Acquire M1-Like Phenotype.

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