Oxygen-Mediated Suppression of CD8+ T Cell Proliferation by Macrophages: Role of Pharmacological Inhibitors of HIF Degradation

Gojković, Miloš; Cunha, Pedro P.; Darmasaputra, Gabriella S.; Barbieri, Laura; Rundqvist, Helene; Veliça, Pedro; Johnson, Randall S.

doi:10.3389/fimmu.2021.633586

Cited by 10 publications

(10 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The generation of NO in the immune system has generally focused on T cells as passive players, where myeloid or tumor cell synthesis has been shown to be a significant suppressor of T-cell activity. Although these data are compelling and borne out by our own ( 8 ) and others studies ( 34 ) of hypoxia-induced myelosuppression of CD8 + T-cell proliferation, it is also clear that NO can be used by different cell types to carry out different processes. In that regard, the data we present here provides evidence that NO is not solely inhibitory, as it can also significantly augment adaptive antitumor immune responses.…”

Section: Discussionmentioning

confidence: 84%

“…NOS1 and NOS3 are calcium-sensitive enzymes, predominantly expressed in neurons and in endothelial cells, respectively, whereas the inducible NOS2 is expressed most highly in immune cells of the myeloid lineage (4). Myeloid cell-derived NO has been shown to, amongst other things, allow the resolution of inflammation through suppressing Tcell responsiveness (5)(6)(7)(8). However, the overall significance and function of endogenous NO synthesis by T cells is still not clearly defined (9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Infiltration of Tumors Is Regulated by T cell–Intrinsic Nitric Oxide Synthesis

Cunha

Bargiela

Minogue

et al. 2022

Cancer Immunology Research

Self Cite

View full text Add to dashboard Cite

Nitric oxide (NO) is a signaling molecule produced by NO synthases (NOS1-3) to control processes such as neurotransmission, vascular permeability, and immune function. Although myeloid cell-derived NO has been shown to suppress T-cell responses, the role of NO synthesis in T cells themselves is not well understood. Here, we showed that significant amounts of NO were synthesized in human and murine CD8+ T cells following activation. Tumor growth was significantly accelerated in a T cell-specific, Nos2-null mouse model. Genetic deletion of Nos2 expression in murine T cells altered effector differentiation, reduced tumor infiltration, and inhibited recall responses and adoptive cell transfer function. These data show that endogenous NO production plays a critical role in T cell-mediated tumor immunity.

show abstract

Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Infiltration of Tumors Is Regulated by T cell–Intrinsic Nitric Oxide Synthesis

Cunha

Bargiela

Minogue

et al. 2022

Cancer Immunology Research

Self Cite

View full text Add to dashboard Cite

show abstract

“… 115 Hypoxia augments macrophage-mediated T-cell suppression in a manner dependent on the expression of HIF-1α and targeting HIF-1α in macrophages can promote the proliferation and activation of CD8 + T cells. 116 TAMs produce TGF-β to support HIF-1α expression in CRC cells, thereby upregulating tribbles pseudokinase 3 (TRIB3), which results in activation of the β-catenin/Wnt signaling pathway. 117 TRIB3 can also reduce tumor-infiltrating T cells by inhibiting STAT 1-mediated CXCL10 transcription by enhancing the epidermal growth factor receptor signaling pathway in CRC.…”

Section: Hypoxia Regulated the Tme Of Crcmentioning

confidence: 99%

Prediction of immunotherapy efficacy and immunomodulatory role of hypoxia in colorectal cancer

et al. 2022

View full text Add to dashboard Cite

Immunotherapy has been used in the clinical treatment of colorectal cancer (CRC); however, most patients fail to achieve satisfactory survival benefits. Biomarkers with high specificity and sensitivity are being increasingly developed to predict the efficacy of CRC immunotherapy. In addition to DNA alteration markers, such as microsatellite instability/mismatch repair and tumor mutational burden, immune cell infiltration and immune checkpoints (ICs), epigenetic changes and no-coding RNA, and gut microbiomes all show potential predictive ability. Recently, the hypoxic tumor microenvironment (TME) has been identified as a key factor mediating CRC immune evasion and resistance to treatment. Hypoxia-inducible factor-1α is the central transcription factor in the hypoxia response that drives the expression of a vast number of survival genes by binding to the hypoxia response element in cancer and immune cells in the TME. Hypoxia regulates angiogenesis, immune cell infiltration and activation, expression of ICs, and secretion of various immune molecules in the TME and is closely associated with the immunotherapeutic efficacy of CRC. Currently, various agents targeting hypoxia have been found to improve the TME and enhance the efficacy of immunotherapy. We reviewed current markers commonly used in CRC to predict therapeutic efficacy and the mechanisms underlying hypoxia-induced angiogenesis and tumor immune evasion. Exploring the mechanisms by which hypoxia affects the TME will assist the discovery of new immunotherapeutic predictive biomarkers and development of more effective combinations of agents targeting hypoxia and immunotherapy.

show abstract

“…At this time, full-thickness skin wounds were constructed on the back of mice, which were then exposed to different oxygen conditions until the wounds healed (Figure 5A). During Oxygen supply is essential to the immune response because every cell in the immune system must perform its function in an environment with a specific level of oxygenation [35][36][37]. As immune cells move through the wound tissue, the availability of oxygen changes rapidly, adapting to the needs of the cells [36].…”

Section: Acute Wound Healing Under Hypoxia In Vivomentioning

confidence: 99%

Reoxygenation Modulates the Adverse Effects of Hypoxia on Wound Repair

Bai¹,

Gao²,

Hu³

et al. 2022

IJMS

View full text Add to dashboard Cite

Hypoxia is a major stressor and a prominent feature of pathological conditions, such as bacterial infections, inflammation, wounds, and cardiovascular defects. In this study, we investigated whether reoxygenation has a protective effect against hypoxia-induced acute injury and burn using the C57BL/6 mouse model. C57BL/6 mice were exposed to hypoxia and treated with both acute and burn injuries and were in hypoxia until wound healing. Next, C57BL/6 mice were exposed to hypoxia for three days and then transferred to normoxic conditions for reoxygenation until wound healing. Finally, skin wound tissue was collected to analyze healing-related markers, such as inflammation, vascularization, and collagen. Hypoxia significantly increased inflammatory cell infiltration and decreased vascular and collagen production, and reoxygenation notably attenuated hypoxia-induced infiltration of inflammatory cells, upregulation of pro-inflammatory cytokine levels (IL-6 and TNF-α) in the wound, and remission of inflammation in the wound. Immunofluorescence analysis showed that reoxygenation increased the expression of the angiogenic factor α-SMA and decreased ROS expression in burn tissues compared to hypoxia-treated animals. Moreover, further analysis by qPCR showed that reoxygenation could alleviate the expression of hypoxic-induced inflammatory markers (IL-6 and TNF), increase angiogenesis (SMA) and collagen synthesis (Col I), and thus promote wound healing. It is suggested that oxygen can be further evaluated in combination with oxygen-releasing materials as a supplementary therapy for patients with chronic hypoxic wounds.

show abstract

Oxygen-Mediated Suppression of CD8+ T Cell Proliferation by Macrophages: Role of Pharmacological Inhibitors of HIF Degradation

Cited by 10 publications

References 31 publications

Infiltration of Tumors Is Regulated by T cell–Intrinsic Nitric Oxide Synthesis

Infiltration of Tumors Is Regulated by T cell–Intrinsic Nitric Oxide Synthesis

Prediction of immunotherapy efficacy and immunomodulatory role of hypoxia in colorectal cancer

Reoxygenation Modulates the Adverse Effects of Hypoxia on Wound Repair

Contact Info

Product

Resources

About