bims-stacyt 2022-05-01 papers

FEBS J. 2022 Apr 29.

Regulation of Intrinsic and Extrinsic Metabolic Pathways in Tumor-Associated Macrophages.

Goutham Venkata Naga Davuluri, Chia-Hsin Chan.

Tumor-associated macrophages (TAMs) are highly plastic and are broadly grouped into two major functional states, namely the pro-inflammatory M1-type and the pro-tumoral M2-type. Conversion of the functional states of TAMs is regulated by various cytokines, chemokines growth factors, and other secreted factors in the microenvironment. Dysregulated metabolism is a hallmark of cancer. Emerging evidence suggests that metabolism governs the TAM differentiation and functional conversation in support of tumor growth and metastasis. Aside from the altered metabolism reprogramming in TAMs, extracellular metabolites secreted by cancer, stromal, and/or other cells within the tumor microenvironment have been found to regulate TAMs through passive competition for metabolite availability and direct regulation via receptor/transporter-mediated signaling reaction. In this review, we focus on the regulatory roles of different metabolites and metabolic pathways in TAM conversion and function. We also discuss if the dysregulated metabolism in TAMs can be exploited for the development of new therapeutic strategies against cancer.

Keywords: immunotherapy; macrophage polarization and conversion; metabolic pathways; tumor-associated macrophages

DOI: https://doi.org/10.1111/febs.16465

J Leukoc Biol. 2022 Apr 25.

Direct and indirect regulation of the tumor immune microenvironment by VEGF.

Yuqing Zhang, Rolf A Brekken.

Vascular endothelial growth factor-A (VEGF) is the predominant angiogenic factor that is expressed in solid tumors. Besides its critical function in mediating tumor angiogenesis, multiple studies have demonstrated that VEGF also contributes to tumor immunosuppression. VEGF interferes with immune cell trafficking indirectly by promoting a vascular immune barrier through VEGF receptor (VEGFR) activity on endothelial cells. However, VEGFRs are also expressed on multiple immune cell types, including T cells (effector T cells, Tregs) and myeloid cells (DCs, TAMs, MDSCs), where VEGF can have direct effects on immune cell phenotype and function. Thus, it is not surprising that strategies targeting VEGF/VEGFRs have shown efficacy in alleviating tumor-associated immunosuppression and have been combined with immunotherapies, especially immune checkpoint blockade. In this review, we discuss the direct and indirect effects of VEGF on the immunosuppressive tumor microenvironment with particular focus on the direct regulation of immune cells through VEGFR2 activity. We also summarize preclinical and clinical observations of combining antiangiogenesis agents with immunotherapies for the treatment of solid tumors.

Keywords: VEGF; angiogenesis; immune regulation; tumor microenvironment

DOI: https://doi.org/10.1002/JLB.5RU0222-082R

PLoS One. 2022 ;17(4): e0266827

Obesity modulates the immune macroenvironment associated with breast cancer development.

Aleida Núñez-Ruiz, Flor Sánchez-Brena, Cynthia López-Pacheco, Naray A Acevedo-Domínguez, Gloria Soldevila.

Growing evidence demonstrates a strong correlation between obesity and an increased risk of breast cancer, although the mechanisms involved have not been completely elucidated. Some reports have described a crosstalk between adipocytes, cancer cells, and immune cells within the tumor microenvironment, however, it is currently unknown whether obesity can promote tumor growth by inducing systemic alterations of the immune cell homeostasis in peripheral lymphoid organs and adipose tissue. Here, we used the E0771 breast cancer cell line in a mouse model of diet-induced obesity to analyze the immune subpopulations present in the tumors, visceral adipose tissue (VAT), and spleen of lean and obese mice. Our results showed a significant reduction in the frequency of infiltrating CD8+ T cells and a decreased M1/M2 macrophage ratio, indicative of the compromised anti-tumoral immune response reported in obesity. Despite not finding differences in the percentage or numbers of intratumoral Tregs, phenotypic analysis showed that they were enriched in CD39+, PD-1+ and CCR8+ cells, compared to the draining lymph nodes, confirming the highly immunosuppressive profile of infiltrating Tregs reported in established tumors. Analysis of peripheral T lymphocytes showed that tumor development in obese mice was associated to a significant increase in the percentage of peripheral Tregs, which supports the systemic immunosuppressive effect caused by the tumor. Interestingly, evaluation of immune subpopulations in the VAT showed that the characteristic increase in the M1/M2 macrophage ratio reported in obesity, was completely reversed in tumor-bearing mice, resembling the M2-polarized profile found in the microenvironment of the growing tumor. Importantly, VAT Tregs, which are commonly decreased in obese mice, were significantly increased in the presence of breast tumors and displayed significantly higher levels of Foxp3, indicating a regulatory feedback mechanism triggered by tumor growth. Altogether, our results identify a complex reciprocal relationship between adipocytes, immune cells, and the tumor, which may modulate the immune macroenvironment that promotes breast cancer development in obesity.

DOI: https://doi.org/10.1371/journal.pone.0266827

J Med Imaging Radiat Oncol. 2022 Apr 24.

Improving the synergistic combination of programmed death-1/programmed death ligand-1 blockade and radiotherapy by targeting the hypoxic tumour microenvironment.

Faiqa Mudassar, Han Shen, Kristina M Cook, Eric Hau.

Immune checkpoint inhibition with PD-1/PD-L1 blockade is a promising area in the field of anti-cancer therapy. Although clinical data have revealed success of PD-1/PD-L1 blockade as monotherapy or in combination with CTLA-4 or chemotherapy, the combination with radiotherapy could further boost anti-tumour immunity and enhance clinical outcomes due to the immunostimulatory effects of radiation. However, the synergistic combination of PD-1/PD-L1 blockade and radiotherapy can be challenged by the complex nature of the tumour microenvironment (TME), including the presence of tumour hypoxia. Hypoxia is a major barrier to the effectiveness of both radiotherapy and PD-1/PD-L1 blockade immunotherapy. Thus, targeting the hypoxic TME is an attractive strategy to enhance the efficacy of the combination. Addition of compounds that directly or indirectly reduce hypoxia, to the combination of PD-1/PD-L1 inhibitors and radiotherapy may optimize the success of the combination and improve therapeutic outcomes. In this review, we will discuss the synergistic combination of PD-1/PD-L1 blockade and radiotherapy and highlight the role of hypoxic TME in impeding the success of both therapies. In addition, we will address the potential approaches for targeting tumour hypoxia and how exploiting these strategies could benefit the combination of PD-1/PD-L1 blockade and radiotherapy.

Keywords: PD-1/PD-L1 blockade; hypoxia; immune suppression; radiotherapy; tumour microenvironment

DOI: https://doi.org/10.1111/1754-9485.13416

JGH Open. 2022 Apr;6(4): 270-273

Effects of SGLT2 inhibitor on tumor-releasing chemokines/cytokines in Hep3B and Huh7 cells.

Dan Nakano, Takumi Kawaguchi, Tsubasa Tsutsumi, Masako Hayakawa, Sachiyo Yoshio, Hironori Koga, Takuji Torimura.

(a) Summary for SGLT2i-induced alterations in 48 chemokines/cytokines in Hep3B and Huh7 cells. (b) SGLT2i-induced changes in the medium CXCL1 level (each n = 4). (c) SGLT2i-induced changes in the medium CXCL8 level (each n = 4). (d) SGLT2i-induced changes in the medium CXCL10 level (each n = 4), (e) SGLT2i-induced changes in the medium M-CSF level (each n = 4). The SGLT2i-induced significant changes in chemokines/cytokines are expressed as the percentage of control (the mean value of the control was set as 100%). CXCL, C-X-C motif chemokine ligand; G-CSF, granulocyte colony-stimulating factor; IL, interleukin; LIF, leukemia inhibitory factor; M-CSF, macrophage colony-stimulating factor; MIP-1α, macrophage inflammatory protein-1α; SDF-1α, stromal-cell-derived factor-1α; TNFα, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.

Keywords: chemokine; cytokine; hepatoma; sodium‐glucose cotransporter 2; tumor microenvironment

DOI: https://doi.org/10.1002/jgh3.12730

Front Biosci (Landmark Ed). 2022 Apr 20. 27(4): 139

Metabolic cross-talk between ovarian cancer and the tumor microenvironment-providing potential targets for cancer therapy.

Yi Lin, Xiao Liang, Xijie Zhang, Yanghong Ni, Xiaoting Zhou, Xia Zhao.

Conventional treatments for ovarian cancer, including debulking cytoreductive surgery combined with carboplatin/paclitaxel-based chemotherapy, are insufficient, as evidenced by the high mortality rate, which ranks first among gynecological tumors. Therefore, there is an urgent need to develop new and effective treatment strategies. Recent evidence has shown that metabolic processes and cell behaviors in ovarian cancer are regulated by intracellular factors as well as metabolites in the tumor microenvironment (TME), which determine occurrence, proliferation, and metastasis. In this review, we describe the comprehensive landscape of metabolic cross-talk between ovarian cancer and its TME with a focus on the following four aspects: (1) intracellular metabolism based on the Warburg effect, (2) metabolism in non-tumor cells in the ovarian TME, (3) metabolic communication between tumor cells and non-tumor cells in the TME, and (4) metabolism-related therapeutic targets and agents for ovarian cancer. The metabolic cross-talk between ovarian cancer and its microenvironment involves a complex network of interactions, and interrupting these interactions by metabolic interventions is a promising therapeutic strategy.

Keywords: cancer therapies; metabolites; ovarian cancer; review; tumor microenvironment

DOI: https://doi.org/10.31083/j.fbl2704139