Tumour-draining axillary lymph nodes in patients with large and locally advanced breast cancers undergoing neoadjuvant chemotherapy (NAC): the crucial contribution of immune cells (effector, regulatory) and cytokines (Th1, Th2) to immune-mediated tumour cell death induced by NAC

Kaewkangsadan, Viriya; Verma, Chandan; Eremin, Jennifer; Cowley, Gerard; Ilyas, Mohammad; Eremin, O.

doi:10.1186/s12885-018-4044-z

Cited by 14 publications

(9 citation statements)

References 84 publications

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“…By contrast, we have observed that high infiltration of CD68 + macrophages correlated with better pathological responses to the treatment in IBC patients, albeit this was not linked to improved overall survival. Similar findings were reported recently for large and locally advanced breast cancer in which high levels of CD163 + tumour-associated macrophages in the tumour tissues were a good predictor for pCR but not for OS [32].…”

Section: Discussionsupporting

confidence: 90%

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

Hayward

Gachehiladze

Badr

et al. 2020

The Journal of Pathology

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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.

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Section: Discussionsupporting

confidence: 90%

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

Hayward

Gachehiladze

Badr

et al. 2020

The Journal of Pathology

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“…In addition, currently, few studies have assessed TILs in metastatic lymph nodes, and a standard assessment method is lacking. Kaewkangsadan et al were the first to evaluate the abundance of TILs, Tregs (FOXP3+, CTLA4+) and NK cells in metastatic axillary lymph nodes (26). The evaluation method for TILs in metastatic lymph nodes still requires further exploration, and a unified standard is lacking for determining the TILs threshold, which requires the consensus of many researchers.…”

Section: Discussionmentioning

confidence: 99%

Changes in Tumor-Infiltrating Lymphocytes and Vascular Normalization in Breast Cancer Patients After Neoadjuvant Chemotherapy and Their Correlations With DFS

Wang

Xiang

et al. 2020

Front. Oncol.

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Objective: Changes in the number of various tumor-infiltrating lymphocytes (TILs) and degrees of vascular normalization in breast cancer (BC) patients after neoadjuvant chemotherapy (NAC) were analyzed to screen key factors that can predict the prognosis. Methods: HE-stained sections were used to assess the degree of TILs infiltration; immunohistochemically stained sections were used to assess the infiltration of CD8+, CD4+, FOXP3+ Tregs and the expression of PD-L1; immunofluorescence-stained sections were used to assess the microvessel density (MVD) and microvessel pericyte coverage index (MPI). The expression of them before NAC were compared with those after NAC, and correlations between changes in these parameters and the pathological complete remission (pCR) and DFS of BC patients were analyzed. Results: After NAC, the percentage of patients with enhanced sTILs in the pCR group was significantly higher than that in the Non-pCR group (P < 0.05). Univariate and multivariate analyses showed that the number of FOXP3+ Tregs and MPI before NAC were correlated with pCR (P < 0.05). Survival analysis showed that the DFS of BC patients with reduced FOXP3+ Tregs was significantly better than that of patients with elevated FOXP3+ Tregs (P = 0.029). The sTILs count and MPI were significantly higher in primary tumors than lymph nodes (P < 0.05). Conclusion: After NAC, the reduced infiltration of FOXP3+ Tregs was correlated with an improvement in DFS in BC patients. Changes in the number of FOXP3+ Tregs and the MPI may be used as prognostic markers for BC patients.

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“…221 Then, the inflammatory, immunological and metabolic processes of the tumor and the tumor-draining lymph nodes (TDLNs), constituting the immunological TME, are also reprogrammed. 222 According to Dvorak's 1986 comment, malignancies are regarded as "wounds that do not heal". 223,224 As an important risk factor for malignancy, chronic immune activation and inflammation persistently promote TME formation by providing inflammatory mediators such as TNF-α, IL-1β, IL-6 and TGF-β and ultimately lead to angiogenesis and antitumor immunity.…”

Section: Ubiquitination In Tumor Metabolism Regulationmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

415

308

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Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

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Tumour-draining axillary lymph nodes in patients with large and locally advanced breast cancers undergoing neoadjuvant chemotherapy (NAC): the crucial contribution of immune cells (effector, regulatory) and cytokines (Th1, Th2) to immune-mediated tumour cell death induced by NAC

Cited by 14 publications

References 84 publications

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

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

Changes in Tumor-Infiltrating Lymphocytes and Vascular Normalization in Breast Cancer Patients After Neoadjuvant Chemotherapy and Their Correlations With DFS

The role of ubiquitination in tumorigenesis and targeted drug discovery

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