| 1. |
- He, Fei, et al.
(author)
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Sex dimorphism in the tumor microenvironment : From bench to bedside and back
- 2022
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In: Seminars in Cancer Biology. - : Elsevier. - 1044-579X .- 1096-3650. ; 86:3, s. 166-179
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Research review (peer-reviewed)abstract
- Cancer represents a significant cause of death and suffering in both the developed and developing countries. Key underlying issues in the mortality of cancer are delayed diagnosis and resistance to treatments. However, improvements in biomarkers represent one important step that can be taken for alleviating the suffering caused by malignancy. Precision-based medicine is promising for revolutionizing diagnostic and treatment strategies for cancer patients worldwide. Contemporary methods, including various omics and systems biology approaches, as well as advanced digital imaging and artificial intelligence, allow more accurate assessment of tumor characteristics at the patient level. As a result, treatment strategies can be specifically tailored and adapted for individual and/or groups of patients that carry certain tumor characteristics. This includes immunotherapy, which is based on characterization of the immunosuppressive tumor microenvironment (TME) and, more specifically, the presence and activity of immune cell subsets. Unfortunately, while it is increasingly clear that gender strongly affects immune regulation and response, there is a knowledge gap concerning differences in sex-specific immune responses and how these contribute to the immunosuppressive TME and the response to immunotherapy. In fact, sex dimorphism is poorly understood in cancer progression and is typically ignored in current clinical practice. In this review, we aim to survey the available literature and highlight the existing knowledge gap in order to encourage further studies that would contribute to understanding both gender-biased immunosuppression in the TME and the driver of tumor progression towards invasive and metastatic disease. The review highlights the need to include sex optimized/genderized medicine as a new concept in future medicine cancer diagnostics and treatments.
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| 2. |
- Sarhan, Dhifaf, et al.
(author)
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Targeting myeloid suppressive cells revives cytotoxic anti-tumor responses in pancreatic cancer
- 2022
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In: ISCIENCE. - : Elsevier BV. - 2589-0042. ; 25:11, s. 105317-
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Journal article (peer-reviewed)abstract
- Immunotherapy for cancer that aims to promote T cell anti-tumor activity has changed current clinical practice, where some previously lethal cancers have now become treatable. However, clinical trials with low response rates have been disappointing for pancreatic ductal adenocarcinoma (PDAC). One suggested explanation is the accumulation of dominantly immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells in the tumor microenvironment (TME). Using retrospectively collected tumor specimens and transcriptomic data from PDAC, we demonstrate that expression of the scavenger receptor MARCO correlates with poor prognosis and a lymphocyte-excluding tumor phenotype. PDAC cell lines produce IL-10 and induce high expression of MARCO in myeloid cells, and this was further enhanced during hypoxic conditions. These myeloid cells suppressed effector T and natural killer (NK) cells and blocked NK cell tumor infiltration and tumor killing in a PDAC 3D-spheroid model. Anti-human MARCO (anti-hMARCO) antibody targeting triggered the repolarization of tumor-associated macrophages and activated the inflammasome machinery, resulting in IL-18 production. This in turn enhanced T cell and NK cell functions. The targeting of MARCO thus remodels the TME and represents a rational approach to make immunotherapy more efficient in PDAC patients.
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