bims-stacyt 2022-02-13 papers

bims-stacyt

Biomed News

on Paracrine crosstalk between cancer and the organism

Issue of 2022‒02‒13
eight papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

Lactic acid, a driver of tumor-stroma interactions.
Blocking EP4 downregulates tumor metabolism and synergizes with anti-PD-1 therapy to activate natural killer cells in a lung adenocarcinoma model.
Low pH up-regulates interleukin-6 mRNA in L6-G8C5 rat skeletal muscle cells independent of pH sensing by SNAT2(SLC38A2) transporters.
Disrupting CANCER angiogenesis and immune checkpoint networks for improved tumor immunity.
CDK4/6 inhibition suppresses p73 phosphorylation and activates DR5 to potentiate chemotherapy and immune checkpoint blockade.
Cadmium induces the expression of Interleukin-6 through Heme Oxygenase-1 in HK-2 cells and Sprague-Dawley rats.
Next steps for clinical translation of adenosine pathway inhibition in cancer immunotherapy.
Itaconate and fumarate derivatives inhibit priming and activation of the canonical NLRP3 inflammasome in macrophages.

Int Immunopharmacol. 2022 Feb 04. pii: S1567-5769(22)00081-9. [Epub ahead of print]106 108597

Lactic acid, a driver of tumor-stroma interactions.

Dun Niu, Yiwen Wu, Ziyao Lei, Ming Zhang, Zhizhong Xie, Shengsong Tang.

  Warburg effect is one of the hallmarks of tumor favoring the suppression of normal oxidative phosphorylation (OxPhos) and the adaptation to hypoxia. In addition to providing continuous energy to meet the demands of tumors, acceleratedWarburg effect also producesa large amount of lactic acid. Lactic acid shuttles between different cell populations within the tumor microenvironment (TME) and confers tumor cells to interact with surrounding cells, which has emerged as a new phenomenon in the field of tumor biology and tumorigenesis. Lactic acid not only fulfills the energetic demands of stromal cells, but becomes a major regulator of their activity by serving as a signaling molecule. Activated stromal cells in turn support tumor development. In this review, we discuss the role of lactic acid in transformation and oncogenic function of stromal cells including fibroblasts, macrophages, adipocytes and vascular endothelial cells, and suggest the relevance of lactic acid in therapy response and essential questions in this field.

Keywords:  Lactic acid; Tumor-associated adipocytes; Tumor-associated fibroblasts; Tumor-associated macrophages; Tumor-associated vascular endothelial cells

DOI:  https://doi.org/10.1016/j.intimp.2022.108597
Int Immunol. 2022 Feb 08. pii: dxac004. [Epub ahead of print]

Blocking EP4 downregulates tumor metabolism and synergizes with anti-PD-1 therapy to activate natural killer cells in a lung adenocarcinoma model.

Miho Tokumasu, Mikako Nishida, Takamasa Kawaguchi, Ikuru Kudo, Tohru Kotani, Kazuhiko Takeda, Takao Yoshida, Heiichiro Udono.

  Prostaglandin E2 (PGE2), a product of the cyclooxygenase (COX) pathway, is produced by tumors and surrounding stromal cells. It stimulates tumor progression, promotes angiogenesis, and suppresses the antitumor response. Pharmacological inhibition of PGE2 synthesis has been shown to suppress tumor initiation and growth in vivo. In the current study, we demonstrated that the growth of the Ptgs2-deficient the 3LL lung adenocarcinoma cell line was downregulated in vivo through natural killer (NK) cell activation and a reduction in the population of polymorphonuclear leukocyte-myeloid-derived suppressor cells (PMN-MDSCs) and tumor associated macrophages (TAMs). Based on these results, the therapeutic effect of ONO-AE3-208 (EP4i), an inhibitor of EP4 (a PGE2 receptor), combined with anti-PD-1Ab was evaluated. EP4i, but not anti-PD-1 Ab, decreased tumor metabolism including glycolysis, fatty acid oxidation, and oxidative phosphorylation. EP4i induced IFNγ production from only NK cells (not from T cells) and a shift from M2- to M1-like macrophages in TAMs. These effects were further enhanced by anti-PD-1 Ab treatment. Although CD8T cell infiltration was increased, IFNγ production was not significantly altered, even with combination therapy. Tumor hypoxia was ameliorated by either EP4i or anti-PD-1 Ab treatment, which was further affected by the combination. Normalization of tumor vessels was significant only for the combination therapy. The results indicate a novel effect of EP4i for the metabolic reprogramming of tumors, revealed unique features of EP4i that can synergize with anti-PD-1Ab to promote IFNγ production of NK cells, polarize TAMs into the M1-phenotype, and reduce hypoxia through normalization of the tumor vasculature. (250 words).

Keywords:  NK cells; Prostaglandin; tumor immunity; tumor metabolism; tumor vessels

DOI:  https://doi.org/10.1093/intimm/dxac004
FASEB Bioadv. 2022 Feb;4(2): 138-152

Low pH up-regulates interleukin-6 mRNA in L6-G8C5 rat skeletal muscle cells independent of pH sensing by SNAT2(SLC38A2) transporters.

Ziyad Aldosari, Nima Abbasian, Katherine Robinson, Alan Bevington, Emma Watson.

  Exercise is known to create a transient, but potent increase in skeletal muscle expression of potentially anti-inflammatory myokine interleukin-6 (IL-6). This effect may be clinically important in managing chronic inflammatory states. It has previously been proposed that lactic acidosis following exercise promotes this IL-6 up-regulation, but the mechanism of this acidosis effect is unknown. Rat skeletal muscle cell line L6-G8C5 has been used previously to model metabolic effects of acidosis, sensing low pH through the resulting inhibition of amino acid transporter SNAT2(SLC38A2). Use of ionophore ionomycin to model the rise in intracellular Ca2+ concentration occurring in contracting muscle strongly up-regulates IL-6 mRNA in L6-G8C5 myotubes. This study used this model to test the hypothesis that low extracellular pH (7.1) enhances ionomycin-induced IL-6 mRNA up-regulation by inhibiting SNAT2. Incubation of L6-G8C5 myotubes for 6 h with 0.5 µM ionomycin at control pH (7.4) resulted in a 15-fold increase in IL-6 mRNA which was further enhanced (1.74-fold) at pH 7.1. In contrast low pH had no significant effect on IL-6 mRNA without ionomycin, nor on the IL-6 mRNA increase that was induced by cyclic stretch. Even though pH 7.1 halved the transport activity of SNAT2, alternative methods of SNAT2 inhibition (JNK inhibitor SP600125; SNAT2 antagonist MeAIB; or SNAT2 silencing with siRNA) did not mimic the enhancing effect of low pH on IL-6 mRNA. On the contrary, JNK inhibition blunted the effect of pH 7.1 with ionomycin, but had no effect at pH 7.4. It is concluded that low pH promotes Ca2+/ionomycin-induced up-regulation of IL-6 mRNA through a novel SNAT2-independent JNK-dependent pH-sensing pathway not previously described in this skeletal muscle model.

Keywords:  JNK; SLC38A2; SNAT2; interleukin‐6 mRNA; pH; skeletal muscle

DOI:  https://doi.org/10.1096/fba.2021-00088
Semin Cancer Biol. 2022 Feb 08. pii: S1044-579X(22)00030-X. [Epub ahead of print]

Disrupting CANCER angiogenesis and immune checkpoint networks for improved tumor immunity.

Trevor S Anderson, Amanda L Wooster, Savanna L Piersall, Izuchukwu F Okpalanwaka, Devin B Lowe.

  Immune checkpoint inhibitors (ICIs) have advanced the field of cancer immunotherapy in patients by sustaining effector immune cell activity within the tumor microenvironment. However, the approach in general is still faced with issues related to ICI response duration/resistance, treatment eligibility, and safety, which indicates a need for further refinements. As immune checkpoint upregulation is inextricably linked to cancer-induced angiogenesis, newer clinical efforts have demonstrated the feasibility of disrupting both tumor-promoting networks to mediate enhanced immune-driven protection. This review focuses on such key evidence stipulating the necessity of co-applying ICI and anti-angiogenic strategies in cancer patients, with particular interest in highlighting newer engineered antibody approaches that may provide theoretically superior multi-pronged and safe therapeutic combinations.

Keywords:  anti-angiogenic strategies; bispecific antibodies; immune checkpoint inhibitors; immune checkpoints; tumor angiogenesis

DOI:  https://doi.org/10.1016/j.semcancer.2022.02.009
Cancer Res. 2022 Feb 11. pii: canres.3062.2021. [Epub ahead of print]

CDK4/6 inhibition suppresses p73 phosphorylation and activates DR5 to potentiate chemotherapy and immune checkpoint blockade.

Jingshan Tong, Xiao Tan, Xiangping Song, Man Gao, Denise Risnik, Suisui Hao, Kaylee Ermine, Peng Wang, Hua Li, Yi Huang, Jian Yu, Lin Zhang.

Targeting cyclin-dependent kinases 4 and 6 (CDK4/6) is a successful therapeutic approach against breast and other solid tumors. Inhibition of CDK4/6 halts cell cycle progression and promotes antitumor immunity. However, the mechanisms underlying the antitumor activity of CDK4/6 inhibitors are not fully understood. We found that CDK4/6 bind and phosphorylate the p53 family member p73 at threonine 86, which sequesters p73 in the cytoplasm. Inhibition of CDK4/6 led to dephosphorylation and nuclear translocation of p73, which transcriptionally activated death receptor 5 (DR5), a cytokine receptor and key component of the extrinsic apoptotic pathway. p73-mediated induction of DR5 by CDK4/6 inhibitors promoted immunogenic cell death (ICD) of cancer cells. Deletion of DR5 in cancer cells in vitro and in vivo abrogated the potentiating effects of CDK4/6 inhibitors on immune cytokine TNF-related apoptosis-inducing ligand (TRAIL), 5-fluorouracil (5-FU) chemotherapy, and anti-PD-1 immunotherapy. Together, these results reveal a previously unrecognized consequence of CDK4/6 inhibition, which may be critical for potentiating the killing and immunogenic effects on cancer cells.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-3062
Food Chem Toxicol. 2022 Feb 02. pii: S0278-6915(22)00043-6. [Epub ahead of print]161 112846

Cadmium induces the expression of Interleukin-6 through Heme Oxygenase-1 in HK-2 cells and Sprague-Dawley rats.

Yen-Chuan Ou, Jian-Ri Li, Chih-Cheng Wu, Tung-Min Yu, Wen-Ying Chen, Su-Lan Liao, Yu-Hsiang Kuan, Yu-Fan Chen, Chun-Jung Chen.

  Cadmium is toxic to the kidney through mechanisms involving oxidative stress and inflammation. We studied reciprocal crosstalk among the oxidative stress, inflammation, and the nuclear Nrf2 pathway in cadmium-induced nephrotoxicity on HK-2 human renal proximal tubular epithelial cells. Cadmium chloride (CdCl2) caused cell viability loss, Reactive Oxygen Species (ROS) generation, glutathione reduction, and Interleukin-6 (IL-6) expression, accompanied by Nrf2 activation and Heme Oxygenase-1 (HO-1) expression. Pharmacological treatments demonstrated cytotprotective and anti-inflammatory effects of Nrf2 activation. Intriguingly, inhibition of HO-1 activity mitigated cell viability loss and IL-6 expression in CdCl2-treated cells. Parallel attenuation by HO-1 inhibitor was demonstrated in cadmium-induced ROS generation and glutathione reduction. CdCl2-treated cells also increased levels of ferrous iron, cGMP, Mitogen-Activated Protein Kinases phosphorylation, as well as NF-κB DNA-binding activity. These increments were mitigated by antioxidant N-Acetyl Cysteine, HO-1 inhibitor SnPP, and PKG inhibitor KT5823, and were mimicked by the Carbon Monoxide-releasing compound. In the kidney cortex of CdCl2-exposed Sprague-Dawley rats, we found similar renal injury, histological changes, ROS generation, IL-6 expression, and accompanied pro-oxidant and pro-inflammatory changes. These observations indicated that cadmium-induced nephrotoxicity was associated with oxidative stress and inflammation, and HO-1 likely acts as a linking molecule to induce nephrotoxicity-associated IL-6 expression upon cadmium exposure.

Keywords:  Cadmium; Heme oxygenase 1; Interleukin-6; Nephrotoxicity; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.fct.2022.112846
J Immunother Cancer. 2022 02;pii: e004089. [Epub ahead of print]10(2):

Next steps for clinical translation of adenosine pathway inhibition in cancer immunotherapy.

Ryan C Augustin, Robert D Leone, Aung Naing, Lawrence Fong, Riyue Bao, Jason J Luke.

  Increasing evidence supports targeting the adenosine pathway in immuno-oncology with several clinical programs directed at adenosine A2 receptor (A2AR, A2BR), CD73 and CD39 in development. Through a cyclic-AMP-mediated intracellular cascade, adenosine shifts the cytokine and cellular profile of the tumor microenvironment away from cytotoxic T cell inflammation toward one of immune tolerance. A perpetuating cycle of tumor cell proliferation, tissue injury, dysregulated angiogenesis, and hypoxia promote adenosine accumulation via ATP catabolism. Adenosine receptor (eg, A2AR, A2BR) stimulation of both the innate and adaptive cellular precursors lead to immunosuppressive phenotypic differentiation. Preclinical work in various tumor models with adenosine receptor inhibition has demonstrated restoration of immune cell function and tumor regression. Given the broad activity but known limitations of anti-programmed cell death protein (PD1) therapy and other checkpoint inhibitors, ongoing studies have sought to augment the successful outcomes of anti-PD1 therapy with combinatorial approaches, particularly adenosine signaling blockade. Preliminary data have demonstrated an optimal safety profile and enhanced overall response rates in several early phase clinical trials with A2AR and more recently CD73 inhibitors. However, beneficial outcomes for both monotherapy and combinations have been mostly lower than expected based on preclinical studies, indicating a need for more nuanced patient selection or biomarker integration that might predict and optimize patient outcomes. In the context of known immuno-oncology biomarkers such as tumor mutational burden and interferon-associated gene expression, a comparison of adenosine-related gene signatures associated with clinical response indicates an underlying biology related to immunosuppression, angiogenesis, and T cell inflammation. Importantly, though, adenosine associated gene expression may point to a unique intratumoral phenotype independent from IFN-γ related pathways. Here, we discuss the cellular and molecular mechanisms of adenosine-mediated immunosuppression, preclinical investigation of adenosine signaling blockade, recent response data from clinical trials with A2AR, CD73, CD39 and PD1/L1 inhibitors, and ongoing development of predictive gene signatures to enhance combinatorial immune-based therapies.

Keywords:  adenosine; gene expression profiling; immune tolerance; tumor microenvironment

DOI:  https://doi.org/10.1136/jitc-2021-004089
Immunology. 2022 Feb 09.

Itaconate and fumarate derivatives inhibit priming and activation of the canonical NLRP3 inflammasome in macrophages.

Christopher Hoyle, Jack P Green, Stuart M Allan, David Brough, Eloise Lemarchand.

  The NLRP3 inflammasome is a multi-protein complex that regulates caspase-1 activation and subsequent interleukin (IL)-1β and IL-18 release from innate immune cells in response to infection or injury. Derivatives of the metabolites itaconate and fumarate, dimethyl itaconate (DMI), 4-octyl itaconate (4OI) and dimethyl fumarate (DMF), limit both expression and release of IL-1β following NLRP3 inflammasome activation. However, the direct effects of these metabolite derivatives on NLRP3 inflammasome responses require further investigation. Using murine bone marrow-derived macrophages, mixed glia and organotypic hippocampal slice cultures (OHSCs), we demonstrate that DMI, 4OI and DMF pre-treatment inhibit pro-inflammatory cytokine production in response to lipopolysaccharide (LPS), as well as inhibiting subsequent NLRP3 inflammasome activation induced by nigericin. DMI, 4OI, DMF and monomethyl fumarate (MMF), another fumarate derivative, also directly inhibited biochemical markers of NLRP3 activation in LPS-primed macrophages, mixed glia, OHSCs and human macrophages in response to nigericin and imiquimod, including ASC speck formation, caspase-1 activation, gasdermin D cleavage and IL-1β release. DMF, an approved treatment for multiple sclerosis, as well as DMI, 4OI and MMF, inhibited NLRP3 activation in macrophages in response to lysophosphatidylcholine, which is used to induce demyelination, suggesting a possible mechanism for DMF in multiple sclerosis through NLRP3 inhibition. The derivatives also reduced pro-IL-1α cleavage in response to the calcium ionophore ionomycin. Together, these findings reveal the immunometabolic regulation of both the priming and activation steps of NLRP3 activation in macrophages. Furthermore, we highlight itaconate and fumarate derivatives as potential therapeutic options in NLRP3- and IL-1α-driven diseases, including in the brain.

Keywords:  NLRP3; fumarate; inflammasome; interleukin; itaconate

DOI:  https://doi.org/10.1111/imm.13454