bims-stacyt 2021-04-11 papers

Cell Rep. 2021 Apr 06. pii: S2211-1247(21)00258-8. [Epub ahead of print]35(1): 108944

Metabolic modulation by CDK4/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors.

Roman V Uzhachenko, Vijaya Bharti, Zhufeng Ouyang, Ashlyn Blevins, Stacey Mont, Nabil Saleh, Hunter A Lawrence, Chengli Shen, Sheau-Chiann Chen, Gregory D Ayers, David G DeNardo, Carlos Arteaga, Ann Richmond, Anna E Vilgelm.

Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) delay progression of metastatic breast cancer. However, complete responses are uncommon and tumors eventually relapse. Here, we show that CDK4/6i can enhance efficacy of T cell-based therapies, such as adoptive T cell transfer or T cell-activating antibodies anti-OX40/anti-4-1BB, in murine breast cancer models. This effect is driven by the induction of chemokines CCL5, CXCL9, and CXCL10 in CDK4/6i-treated tumor cells facilitating recruitment of activated CD8+ T cells, but not Tregs, into the tumor. Mechanistically, chemokine induction is associated with metabolic stress that CDK4/6i treatment induces in breast cancer cells. Despite the cell cycle arrest, CDK4/6i-treated cells retain high metabolic activity driven by deregulated PI3K/mTOR pathway. This causes cell hypertrophy and increases mitochondrial content/activity associated with oxidative stress and inflammatory stress response. Our findings uncover a link between tumor metabolic vulnerabilities and anti-tumor immunity and support further development of CDK4/6i and immunotherapy combinations.

Keywords: CCL5; CDK4/6 inhibitors; ROS; adoptive cell transfer; anti-tumor immunity; cancer metabolism; chemokines; metabolic stress; palbociclib

DOI: https://doi.org/10.1016/j.celrep.2021.108944

Nature. 2021 Apr 07.

Cell-programmed nutrient partitioning in the tumour microenvironment.

Cancer cells characteristically consume glucose through Warburg metabolism1, a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells2-4. However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME.

DOI: https://doi.org/10.1038/s41586-021-03442-1

Sci Rep. 2021 Apr 08. 11(1): 7689

Interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma.

Toshiyuki Seki, Nozomu Yanaihara, Jason Solomon Shapiro, Misato Saito, Junya Tabata, Ryo Yokomizo, Daito Noguchi, Takafumi Kuroda, Ayako Kawabata, Jiro Suzuki, Kazuaki Takahashi, Haruka Matsuzawa, Misayo Miyake, Masataka Takenaka, Yasushi Iida, Satoshi Yanagida, Aikou Okamoto.

Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) that is associated with elevated interleukin-6 (IL-6) expression, resistance to chemotherapy, and increased mortality. Although bevacizumab (Bev) is a widely used anti-angiogenic agent for EOC, the efficacy of Bev and the role of IL-6 in modulating angiogenesis in OCCC are unknown. We performed tube formation assays using human umbilical vein endothelial cells (HUVEC) cultured in OCCC cell-conditioned medium and using cells directly co-cultured with OCCC cells. We observed that IL-6 inhibition significantly mitigated the ability of Bev to impede tube formation in both cases. Furthermore, IL-6 blockade disrupted the anti-angiogenic efficacy of Bev and its concomitant anti-tumor activity. In addition, IL-6 inhibition resulted in a significant increase in angiopoietin-1 (Ang1) secretion and decreased vascular endothelial growth factor (VEGF) expression. Clinical specimens also exhibited this reciprocal relationship between IL-6 and Ang1 expression. Finally, depletion of Ang1 abrogated the effects of IL-6 inhibition on Bev activity, demonstrating that IL-6 supports the anti-angiogenic activity of Bev by suppressing Ang1 expression and promoting dependence on VEGF for angiogenesis. Altogether, our data suggest that OCCC tumors with high IL-6 levels are candidates for Bev therapy.

DOI: https://doi.org/10.1038/s41598-021-86913-9

Mol Cell. 2021 Apr 04. pii: S1097-2765(21)00214-8. [Epub ahead of print]

Immune-regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells.

Alice Clare Newman, Mattia Falcone, Alejandro Huerta Uribe, Tong Zhang, Dimitris Athineos, Matthias Pietzke, Alexei Vazquez, Karen Blyth, Oliver David Kenneth Maddocks.

Cancer cells adapt their metabolism to support elevated energetic and anabolic demands of proliferation. Folate-dependent one-carbon metabolism is a critical metabolic process underpinning cellular proliferation supplying carbons for the synthesis of nucleotides incorporated into DNA and RNA. Recent research has focused on the nutrients that supply one-carbons to the folate cycle, particularly serine. Tryptophan is a theoretical source of one-carbon units through metabolism by IDO1, an enzyme intensively investigated in the context of tumor immune evasion. Using in vitro and in vivo pancreatic cancer models, we show that IDO1 expression is highly context dependent, influenced by attachment-independent growth and the canonical activator IFNγ. In IDO1-expressing cancer cells, tryptophan is a bona fide one-carbon donor for purine nucleotide synthesis in vitro and in vivo. Furthermore, we show that cancer cells release tryptophan-derived formate, which can be used by pancreatic stellate cells to support purine nucleotide synthesis.

Keywords: IDO1; IFNγ; PDAC; cancer immunology; cancer metabolism; epacadostat; formate; immunometabolism; immunotherapy; one-carbon metabolism; pancreas; serine; stellate cells; tryptophan; tumor microenvironment

DOI: https://doi.org/10.1016/j.molcel.2021.03.019