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Muthana, M.

Publications and source records attributed to Muthana, M..

2 recordsLinked to original sources
bioRxiv2024

Targeting of a STING Agonist to Perivascular Macrophages in Prostate Tumors Delays Resistance to Androgen Deprivation Therapy

BackgroundAndrogen deprivation therapy (ADT) is a frontline treatment for prostate cancer but often leads to the development of castration resistant prostate cancer (CRPC). This causes tumors to regrow and metastasize, despite ongoing treatment, and impacts negatively on patient survival. ADT is known to stimulate the accumulation of immunosuppressive cells like protumoral tumor-associated macrophages (TAMs), myeloid-derived suppressor cells and regulatory T cells in prostate tumors, as well as hypofunctional T cells. Protumoral TAMs have been shown to accumulate around tumor blood vessels during chemotherapy and radiotherapy, where they drive tumor relapse. Our aim was to see if such perivascular (PV) TAMs accumulated in ADT-treated prostate tumors prior to CRPC, and, if so, to selectively target these PV cells with a potent immunostimulant, interferon beta (IFN{beta}), an attempt to stimulate anti-tumor immunity and delay CRPC. MethodsWe first used quantitative, multiplex immunofluorescence to assess the effects of ADT on distribution and activation status of TAMs, CD4+ T cells, CD8+ T cells and NK cells in mouse and human prostate tumors. We then used antibody-coated, lipid nanoparticles to selectively target a STING agonist, 2'3'-cGAMP (cGAMP), to PV TAMs in mouse prostate tumors during ADT. ResultsTAMs accumulated at high density around blood vessels in ADT-treated primary mouse and human prostate tumors prior to CRPC, where they expressed markers of a protumoral phenotype, folate receptor beta (FR{beta}), MRC1 (CD206), SIGLEC1 (CD169) and VISTA. Additionally, higher numbers of inactive (PD-1-) CD8+ T cells and reduced numbers of active (CD69+) NK cells were also present in PV tumor areas after ADT. LNPs coated with antibody to FR{beta} selectively delivered cGAMP to PV TAMs in ADT-treated tumors where they activated STING and expression of IFN{beta} by these cells. This resulted in a marked increase in the density of active CD4+ T cells, CD8+T cells and NK cells in PV tumor areas, and significantly delayed in the onset of CRPC. ConclusionTogether, our data indicate that targeting a STING agonist to PV TAMs could be used to extend the treatment window for ADT in prostate cancer. KEY MESSAGESO_ST_ABSWhat is already known about the topicC_ST_ABSAndrogen deprivation therapy (ADT) is a frontline treatment for prostate cancer. However, tumors often develop resistance and start to regrow and metastasize - a condition called castration resistance prostate cancer (CRPC). Prostate cancer is considered to be an immunologically cold tumor type and while ADT stimulates tumor infiltration by cytotoxic (CD8+) T cells, they are largely hypofunctional, possibly due to the immunosuppressive tumor microenvironment. What this study addsThis study is the first to demonstrate that FR{beta}+ macrophages with a immunosuppressive phenotype accumulate around blood vessels in mouse and human prostate tumors during ADT, prior to the onset of CRPC. Lipid nanoparticles coated with an antibody to FR{beta}+ were then used to deliver a STING agonist selectively to these perivascular (PV) cells during ADT. This triggered STING signalling and the release of the potent immunostimulant, interferon beta, by PV macrophages, which then activated tumour-infiltrating CD4+ and CD8+ T cells, and delayed the onset of CRPC. How this study might affect research, practice or policyThe delivery of an immunostimulant specifically to PV regions of tumors represents a new, more targeted form of immunotherapy that ensures the activation of T cells as soon as they cross the vasculature into tumors. This new approach could be used to extend the treatment window for neoadjuvant ADT in men with localised prostate tumors. In doing so, it would delay/circumvent the need for additional treatments like radiotherapy and/or or prostatectomy.

cancer biology↗
bioRxiv2021

TRIB1 regulates tumour growth via controlling tumour-associated macrophage phenotypes and is associated with breast cancer survival and treatment response

Molecular mechanisms that regulate tumour-associated macrophage (TAM) phenotype and function are incompletely understood. Here, we show that the pseudokinase TRIB1 is highly expressed by TAMs in breast cancer and that its expression correlates with response to chemotherapy and patient survival. We used immune-competent murine models of breast cancer to characterise the consequences of altered (reduced or elevated) myeloid Trib1 expression on tumour growth and composition of stromal immune cells. We found that both overexpression and knockout of myeloid Trib1 promote tumour growth, albeit through distinct molecular mechanisms. Myeloid Trib1 deficiency resulted in an early accelearation of tumour growth, paired with a selective reduction in perivascular macrophage numbers in vivo and enhanced oncogenic cytokine expression in vitro. In contrast, elevated levels of Trib1 in myeloid cells led to an increase in mammary tumour volume at late stages, together with a reduction of NOS2 expressing macrophages and an overall reduction of these cells in hypoxic tumour regions. In addition, we show that myeloid Trib1 is a previously unknown, negative regulator of the anti-tumour cytokine IL-15 and that increased expression of myeloid Trib1 leads to reduced IL-15 levels in mammary tumours, with a consequent reduction in the number of T-cells, that are key to anti-tumour immune responses. Together, these results define the different roles of TRIB1 in human breast cancer and provide a mechanistic understanding for the importance of myeloid TRIB1 expression levels in the development of this disease. SignificanceTRIB1 expression is strongly associated with response to chemotherapy in breast cancer patients with aggressive tumours. This protein is also highly expressed by tumour-associated macrophages. Thus, we used myeloid-specific alterations of Trib1 expression in mice (Trib1mKO and Trib1mTg), and characterised consequent changes in the growth rate and tumour microenvironment of mammary tumours. Both Trib1mKO and Trib1mTg enhanced tumour growth, but at different stages of tumour growth and via distinct mechanisms. Trib1mKO significantly increased the expression of oncogenic cytokines, such as IL6, IL10, CCL20, PD-L1, and VEGF. In contrast, Trib1mTg accelerated at the later stage of tumour growth via inhibition of hypoxic TAMs in the TME, as well as by reduced IL-15 expression thus leading to impaired naive and cytotoxic T cell infiltration. These data define TRIB1 as a potential novel marker of therapeutic responses in breast cancer, as well as a key mechanistic regulator of the anti-tumour cytokine, IL-15 in myeloid cells.

cancer biology↗