The international American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumour-node-metastasis (TNM) staging system provides the current guidelines for the classification of cancer. However, among patients within the same stage, the clinical outcome can be very different. More recently, a novel definition of cancer has emerged, implicating at all stages a complex and dynamic interaction between tumour cells and the immune system. This has enabled the definition of the immune contexture, representing the pre-existing immune parameters associated with patient survival. Even so, the role of distinct immune cell types in modulating cancer progression is increasingly emerging. An immune-based assay named the 'Immunoscore' was defined to quantify the in situ T cell infiltrate and was demonstrated to be superior to the AJCC/UICC TNM classification for patients with colorectal cancer. This Review provides a broad overview of the main immune parameters positively or negatively shaping cancer development, including the Immunoscore, and their prognostic and predictive value. The importance of the immune system in cancer control is demonstrated by the requirement for a pre-existing intratumour adaptive immune response for effective immunotherapies, such as checkpoint inhibitors. Finally, we discuss how the combination of multiple immune parameters, rather than individual ones, might increase prognostic and/or predictive power.

The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy.

Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the ...

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TGF-β1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis

B cell and B cell-related pathways for novel cancer treatments.

Disruption of systemic homeostasis by either chronic or acute stressors, such as obesity1 or surgery2, alters cancer pathogenesis. Patients with cancer, particularly those with breast cancer, can be at increased risk of cardiovascular disease due to treatment toxicity and changes in lifestyle behaviors3-5. While elevated risk and incidence of cardiovascular events in breast cancer is well established, whether such events impact cancer pathogenesis is not known. Here we show that myocardial infarction (MI) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6Chi monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in both the circulation and tumor. In parallel, MI increased circulating Ly6Chi monocyte levels and recruitment to tumors and depletion of these cells abrogated MI-induced tumor growth. Furthermore, patients with early-stage breast cancer who experienced cardiovascular events after cancer diagnosis had increased risk of recurrence and cancer-specific death. These preclinical and clinical results demonstrate that MI induces alterations in systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.

Myocardial infarction accelerates breast cancer via innate immune reprogramming

Epithelial-mesenchymal transition in cancer metastasis through the lymphatic system.

We investigated the expression of –CXC chemokine ligand 13 (CXCL13) and its receptor –CXC chemokine receptor 5 (CXCR5) in 98 breast cancer (BC) patients with infiltrating duct carcinoma, out of which 56 were found lymph node metastasis (LNM) positive. Interestingly, co-expression of CXCL13 and CXCR5 showed a significant correlation with LNM. Since, epithelial to mesenchymal transition (EMT) is highly associated with metastasis we investigated EMT-inducing potential of CXCL13 in BC cell lines. In CXCL13-stimulated BC cells, expression of various mesenchymal markers (Vimentin, N-cadherin), EMT regulators (Snail, Slug), and matrix metalloproteinase-9 (MMP9) was increased, whereas the expression of epithelial marker E-cadherin was found to be decreased. In addition, expression of receptor activator of nuclear factor kappa-B ligand (RANKL), which is known to regulate MMP9 expression via Src activation, was also significantly increased after CXCL13 stimulation. Using specific protein kinase inhibitors, we confirmed that CXCL13 stimulated EMT and MMP9 expression via RANKL–Src axis in BC cell lines. To further validate this observation, we examined gene expression patterns in primary breast tumors and detected significantly higher expression of various mesenchymal markers and regulators in CXCL13–CXCR5 co-expressing patients. Therefore, this study showed the EMT-inducing potential of CXCL13 as well as demonstrated the prognostic value of CXCL13–CXCR5 co-expression in primary BC. Moreover, CXCL13–CXCR5–RANKL–Src axis may present a therapeutic target in LNM positive BC patients.

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Vivek Malhotra

Papers

CXCL13–CXCR5 co-expression regulates epithelial to mesenchymal transition of breast cancer cells during lymph node metastasis