https://cancerbiologyprogram.med.wayne.edu/pdfs/hallmarks_cancer_article.pdf

Hallmarks of cancer: the next generation.

The basic elements of the transforming growth factor-β (TGFβ) pathway were revealed more than a decade ago. Since then, the concept of how the TGFβ signal travels from the membrane to the nucleus has been enriched with additional findings, and its multifunctional nature and medical relevance have relentlessly come to light. However, an old mystery has endured: how does the context determine the cellular response to TGFβ? Solving this question is key to understanding TGFβ biology and its many malfunctions. Recent progress is pointing at answers.

/pdf/tgfb-signalling-in-context-56apiue88r.pdf

TGFβ signalling in context.

Cancers are not just masses of malignant cells but complex ‘rogue’ organs, to which many other cells are recruited and can be corrupted by the transformed cells. Interactions between malignant and non-transformed cells create the tumor microenvironment (TME). The non-malignant cells of the TME

The tumor microenvironment at a glance

The development of tumor-specific T cell tolerance is largely responsible for tumor escape. Accumulation of myeloid-derived suppressor cells (MDSCs) in animal tumor models as well as in cancer patients is involved in tumor-associated T cell tolerance. In recent years, it has become increasingly evident that MDSCs bring about antigen-specific T cell tolerance by various mechanisms, which is the focus of this chapter.

https://cancerimmunolres.aacrjournals.org/content/canimm/5/1/3.full.pdf

Myeloid-Derived Suppressor Cells

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets.

/pdf/neutrophils-in-cancer-neutral-no-more-2eb9s218qg.pdf

Neutrophils in cancer: neutral no more

https://www.cell.com/trends/immunology/pdf/S1471-4906(10)00053-0.pdf

TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression

The mechanisms by which a primary tumor affects a selected distant organ before tumor cell arrival remain to be elucidated. This report shows that Gr-1+CD11b+ cells are significantly increased in lungs of mice bearing mammary adenocarcinomas before tumor cell arrival. In the premetastatic lungs, these immature myeloid cells significantly decrease IFN-gamma production and increase proinflammatory cytokines. In addition, they produce large quantities of matrix metalloproteinase 9 (MMP9) and promote vascular remodeling. Deletion of MMP9 normalizes aberrant vasculature in the premetastatic lung and diminishes lung metastasis. The production and activity of MMP9 is selectively restricted to lungs and organs with a large number of Gr-1+CD11b+ cells. Our work reveals a novel protumor mechanism for Gr-1+CD11b+ cells that changes the premetastatic lung into an inflammatory and proliferative environment, diminishes immune protection, and promotes metastasis through aberrant vasculature formation. Thus, inhibition of Gr-1+CD11b+ cells could normalize the premetastatic lung environment, improve host immunosurveillance, and inhibit tumor metastasis.

https://cancerres.aacrjournals.org/content/canres/70/15/6139.full.pdf

Gr-1+CD11b+ Myeloid Cells Tip the Balance of Immune Protection to Tumor Promotion in the Premetastatic Lung

TGFβ is over expressed in advanced human cancers It correlates with metastasis and poor prognosis However, TGFβ functions as both a tumor suppressor and a tumor promoter Here we report for the first time that genetic deletion of Tgfbr2 specifically in myeloid cells (Tgfbr2MyeKO) significantly inhibited tumor metastasis Reconstitution of tumor-bearing mice with Tgfbr2MyeKO bone marrow recapitulates the inhibited metastasis phenotype This effect is mediated through decreased production of type 2 cytokines, TGFβ1, arginase 1 and iNOS, which promoted IFN-γ production and improved systemic immunity Depletion of CD8 T cells diminished metastasis defect in the Tgfbr2MyeKO mice Consistent with animal studies, myeloid cells from advanced stage cancer patients demonstrated an increased TGFβ receptor II expression Our studies demonstrate that myeloid-specific TGFβ signaling is an essential component of the metastasis-promoting puzzle of TGFβ This is in contrast to the previously reported tumor-suppressing phenotypes in fibroblasts, epithelial or T cells

https://cancerdiscovery.aacrjournals.org/content/candisc/3/8/936.full.pdf

TGF-β Signaling in Myeloid Cells Is Required for Tumor Metastasis

Chemokines and chemokine receptors have critical roles in cancer metastasis and have emerged as one of the targeting options in cancer therapy. However, the treatment efficacy on both tumor and host compartments needs to be carefully evaluated. Here we report that targeting CXCR3 decreased tumor cell migration and at the same time improved host anti-tumor immunity. We observed an increased expression of CXCR3 in metastatic tumor cells compared to those from non-metastatic tumor cells. Knockdown (KD) of CXCR3 in metastatic tumor cells suppressed tumor cell migration and metastasis. Importantly, CXCR3 expression in clinical breast cancer samples correlated with progression and metastasis. For the host compartment, deletion of CXCR3 in all host cells in 4T1 mammary tumor model significantly decreased metastasis. The underlying mechanisms involve a decreased expression of IL-4, IL-10, iNOs, and Arg-1 in myeloid cells and an increased T cell response. IFN-γ neutralization diminished the metastasis inhibition in the CXCR3 knockout (KO) mice bearing 4T1 tumors, suggesting a critical role of host CXCR3 in immune suppression. Consistently, targeting CXCR3 using a small molecular inhibitor (AMG487) significantly suppressed metastasis and improved host anti-tumor immunity. Our findings demonstrate that targeting CXCR3 is effective in both tumor and host compartments, and suggest that CXCR3 inhibition is likely to avoid adverse effects on host cells.

/pdf/cxcr3-as-a-molecular-target-in-breast-cancer-metastasis-17piihsvkn.pdf

CXCR3 as a molecular target in breast cancer metastasis: inhibition of tumor cell migration and promotion of host anti-tumor immunity

One great challenge in our understanding of TGF-β cancer biology and the successful application of TGF-β-targeted therapy is that TGF-β works as both a tumor suppressor and a tumor promoter. The underlying mechanisms for its functional change remain to be elucidated. Using 4T1 mammary tumor model that shares many characteristics with human breast cancer, particularly its ability to spontaneously metastasize to the lungs, we demonstrate that Gr-1+CD11b+ cells or myeloid derived suppressor cells are important mediators in TGF-β regulation of mammary tumor progression. Depletion of Gr-1+CD11b+ cells diminished the antitumor effect of TGF-β neutralization. Two mechanisms were involved: first, treatment with TGF-β neutralization antibody (1D11) significantly decreased the number of Gr-1+CD11b+ cells in tumor tissues and premetastatic lung. This is mediated through increased Gr-1+CD11b+ cell apoptosis. In addition, 1D11 treatment significantly decreased the expression of Th2 cytokines and Arginase 1. Interestingly, the number and property of Gr-1+CD11b+ cells in peripheral blood/draining lymph nodes correlated with tumor size and metastases in response to 1D11 treatment. Our data suggest that the efficacy of TGF-β neutralization depends on the presence of Gr-1+CD11b+ cells, and these cells could be good biomarkers for TGF-β-targeted therapy.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.27572

Yanli Pang

Papers

TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression

Gr-1+CD11b+ Myeloid Cells Tip the Balance of Immune Protection to Tumor Promotion in the Premetastatic Lung

TGF-β Signaling in Myeloid Cells Is Required for Tumor Metastasis

CXCR3 as a molecular target in breast cancer metastasis: inhibition of tumor cell migration and promotion of host anti-tumor immunity

Gr-1+CD11b+ cells are responsible for tumor promoting effect of TGF-β in breast cancer progression.