Introduction. Several studies have applied gene expression profiling to inflammatory breast cancer (IBC). Most of these studies were underpowered. Here, we present an integrated analysis of 3 distinct gene expression data sets of IBC and non-IBC (nIBC) samples to further uncover the IBC-specific molecular biology with enhanced statistical power. Materials & Methods. Three Affymetrix gene expression data sets were combined, resulting in a series of 137 IBC and 252 nIBC samples. IBC was diagnosed clinically. Each sample was classified according to several published gene signatures. Transcriptional heterogeneity was investigated using hierarchical clustering, coupled with silhouette score analysis. IBC-specific, molecular subtype-independent differences in gene expression were identified using linear regression modeling. Differentially expressed genes were translated into pathways using Ingenuity Pathway Analysis. Cox regression analysis was used to identify variables influencing distant metastasis-free survival (DMFS) in IBC. Finally, we focussed on the molecular aspects of pathological response to neodjuvant chemotherapy in patients with IBC. Results. In our series of IBC samples, 4 robust sample clusters were identified. These sample clusters were mainly associated with the different molecular subtypes (P<0.0001), all of which were identified in IBC with a similar prevalence in nIBC, except for the Luminal A subtype (9% vs. 40%; P<0.0001) and the ErbB2+ subtype (23% vs. 8%; P=0.0002). A total of 632 genes were differentially expressed. Analysis of this gene list identified an IBC-repressed network centered on TGFβ. Activated TGFβ-profiles and SMAD-profiles in the nIBC samples corroborated these findings. Consistent with published poor prognosis signatures, current survival analysis indicated that the molecular subtypes are significantly associated with prognosis in IBC. Surprisingly, in IBC, the Luminal A samples exhibited the shortest DMFS-interval (HR=4.02; P<0.05). Comparison of responders and non-responders to neoadjuvant chemotherapy suggests a prominent role for inflammation/immunity-related processes in determining the efficacy of neoadjuvant chemotherapy in IBC. Conclusions. IBC, like nIBC, is transcriptionally heterogeneous as exemplified by the identification of 4 robust sample clusters in the present series. This observation is further corroborated by the identification of all known molecular subtypes in IBC, albeit with a different distribution pattern characterized by a low frequency of Luminal A samples. Nevertheless, this phenotype is clinically relevant, as demonstrated by the poor prognosis profile. Our observations can be explained by the IBC-specific repression of TGFβ, which is a key molecule of epithelial-to-mesenchymal transition and is also known to prevent ER-expressing cells from proliferating. Finally, as in nIBC, inflammation- and immunity-related processes are important aspects of response to neoadjuvant chemotherapy in IBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD03-01.
The tumor microenvironment is a dynamic network of stromal, cancer and immune cells that interact and compete for resources. Mitochondria play an essential role in the control of metabolic plasticity and contribute to tumor progression and immune cell functionality. We previously identified the Vanin1 pathway as a tumor suppressor of sarcoma development via vitamin B5 and coenzyme A regeneration. Using an aggressive sarcoma cell line that lacks Vnn1 expression, we showed that administration of pantethine, a vitamin B5 precursor, impairs tumor growth in immunocompetent mice. Pantethine boosts anti-tumor type 1 immunity including polarization of myeloid and dendritic cells towards enhanced IFNγ-driven antigen presentation pathways and improved development of hypermetabolic effector CD8+ T cells endowed with potential anti-tumor activity. At later stages of treatment, the effect of pantethine is limited by the development of immune cell exhaustion. Nevertheless, its activity is comparable to that of anti-PD1 treatment in sensitive tumors. In humans, VNN1 expression correlates with improved survival and immune cell infiltration in soft tissue sarcomas but not osteosarcomas. Pantethine could be a potential therapeutic immunoadjuvant for the development of anti-tumor immunity.
Background Soft tissue sarcomas (STS) are heterogeneous and pro-metastatic tumors. Identification of accurate prognostic factors and novel therapeutic targets are crucial. CSPG4 is a cell surface proteoglycan with oncogenic functions. It recently emerged as a potential target for immunotherapy, including cell therapy based on CSPG4-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CSPG4-CAR.CIKs) in STS. However, expression of CSPG4 is poorly known in STS so far. Methods We analyzed CSPG4 gene expression in 1378 localized STS clinical samples, and searched for correlations with clinicopathological data, including disease-free survival (DFS), and with tumor immune features. Results CSPG4 expression was heterogeneous across samples. High expression was associated with younger patients’ age, more frequent undifferentiated pleomorphic sarcoma and myxofibrosarcoma pathological subtypes, more frequent internal trunk tumor site, and more CINSARC high-risk samples. No correlation existed with pathological tumor size and grade, and tumor depth. Patients with high CSPG4 expression displayed 49% (95% CI 42–57) 5-year DFS versus 61% (95% CI 56–68) in patients with low expression (p = 3.17E−03), representing a 49% increased risk of event in the “CSPG4-high” group (HR = 1.49, 95% CI 1.14–1.94). This unfavorable prognostic value persisted in multivariate analysis, independently from other variables. There were significant differences in immune variables between “CSPG4-high” and “CSPG4-low” tumors. The "CSPG4-low" tumors displayed profiles suggesting higher anti-tumor cytotoxic immune response and higher potential vulnerability to immune checkpoint inhibitors (ICI). By contrast, the "CSPG4-high" tumors displayed profiles implying an immune-excluded tumor microenvironment, potentially induced by hypoxia, resulting from an immature chaotic microvasculature, and/or the presence of contractile myofibroblasts. Conclusions Patients with “CSPG4-high” STS, theoretically candidate for CAR.CIKs, display shorter DFS and an immune environment unfavorable to vulnerability to CAR.CIKs, which could be improved by combining anti-angiogenic drugs able to normalize the tumor vasculature. By contrast, “CSPG4-low” STS are better candidates for immune therapy involving ICI.
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