Cell-programmed nutrient partitioning in the tumour microenvironment.

Cell-programmed nutrient partitioning in the tumour microenvironment.

Cite: Reinfeld, Bradley I., et al. “Cell-programmed nutrient partitioning in the tumour microenvironment.” Nature 593.7858 (2021): 282-288.

Abstract

PET could use for toumor image.

Cacncer Cell Marker: Glucose intacke; Lactate generated (Warburg metabolism)
So as the umour-infltrating immune cells.
As a result, the immune cell was restricted and evaluated.

Thesis: immune cells dysregulated: cell-intrinsic programs or by competition?

Our Solution:

• PET: tracers to measure the access to and uptake of glucose and glutamine

Result:

• Intratumoral glucose:
  • myeloid cells > T cells > Cancer cells
• cancer cells
  • Cancer Cell > all other cells

Hypothesis:

• Metabolism in Result was:
  • Programmed in cell-intrinsic manner through mTORC1 and related genes.

Variation:

• tumour-resident cell: glutamine↓ → glucose↑
• glutamine metabolism → glucose uptake↑

Conclusion: 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 specifc cell populations in the TME.

Intro

Cancer cell; Rapidly proliferating cell, and activated immune cells: convert glucose to lactate very quickly.

FDG PET imaging to detect cancer

Resutl

Figures	Illustration
A, B	human renal cell carcinoma (RCC) and mouse subcutaneous MC38 tumours the mass spectrometry resutl
C, D	FDG PET on mouse
E	CD45⁺: Immune Cells CD45¯ in Tumour Cells
F	High FDG signle in Tumor cells. FDG in immune cell: CD45⁺ > CD45¯
G, H	CD45⁺ immune cells have No spatial distribution favouring
I, J	Same result shows in in mouse subcutaneous CT26 and renal carcinoma (Renca) tumours
K	orthotopic Renca tumours: FDG↑ in immune cells as compared to CD45¯ tumour cells
I	mouse model (GEMM) of breast cance has similar result

Myeloid cells take up the most glucose

Figures	Illustration
A, B	FDG: TME T cells > splenic T cells; TME T cells ≈ cancer cell suggesting that these cells are not deprived of glucose
C, D	myeloid cells (non-T cell CD45⁺ cells; CD11B⁺ selection) were isolated FDG: CD11B⁺ myeloid cells > immune cells in MC38 tumors > cancer cells
E	Two domain, LY6G−LY6Chi cells, from CD45⁺ CD11B⁺ MC38 tumour
F	Isolated F4/80hi cells had a histiocytic morpholog
G, H	high FDG avidity: M-MDSCs by microbeads(GR1⁺) TAMs by microbeads(F4/80⁺)
I-K	extracellular flux assays; ECAR; OCR TAMs and M-MDSCs consume the most glucose per
cell in the TME and maintain robust glucose metabolism.

mTORC1 programs metabolism in the TME

mTORC1: supports anabolic metabolism and nutrient uptake
pS6: monitor the mTORC1 pathway activity in tumour myeloid cells

CD11B+ myeloid cells

Cell type:

• Other CD45⁺ Cell: T cell CD45+ c :: To characterize the non-T cell CD45⁺ cells, myeloid CD11B⁺ (microbeads).

• CD3⁺: CD3⁺ T cells

• CD4⁺: CD4⁺ T cells)

• CD8⁺: CD8⁺ T cells

• CD11B⁺/CD45⁺: Myeloid:

• CD14; CA9

The hypothesis is mTORC1 which supports anabolic metabolism and nutrient uptake. pS6 is a protein which under the upstream of the mTOR signal pathway. Rapamycin can suppress the pS6 without affect the tumor’s weight, concentrations of glucose, glutamine; lactate in the TME; but led to significant decreases in pS6 levels, T cell infiltration, Ki67 levels in cancer cells and T cells, and the cell size of TAMs (Fig. 3d). Treatment with rapamycin also resulted in significant decreases in FDG uptake in myeloid and cancer cells.
f, g, h show that Rapa led to a in myeloid cell metabolism ex vivo, whereas cancer cells and T cells remained unchanged

decrease in myeloid cell metabolism
ex vivo, whereas cancer cells and T cells remained unchanged

Hk1 was broadly expresse, Hk2, the hexokinase isoforms 2, rate-limiting step of glycolysis was highly expressed in myeloid cells.

iron transporter CD71 and the amino acid transporter CD98

This has implications for metabolism-directed agents as
well as therapies that target myeloid cells, with the potential to either enhance or impair tumour-related inflammation. TME-resident cells have the capacity to increase glucose uptake like upreguate the mTOR singal pathway.

Veh? : spleen vehicle; rapamycin- and the vehicle-treated samples; 8 mice for CD4+/CD8+ vehicle; glutamine plasma and TIF vehicle(5% Tween‐80, 5% PEG‐40??),

Figures	Illustration
A	FMO, PBMC, and ccRCC Ridgelines Different pS6 PE expression level in different group of cells.
B
C	mouse MC38 tumours
D	mice bearing MC38 tumours: rapamycin (4 days) → measured FDG uptake Rapamycin did not affect: weight; concentrations of glucose, glutamine; lactate in the TME but pS6↓ significant, T cell infiltration↓, Ki67 levels↓ in cancer cells and T cells, and the cell size↓ of TAMs
E	MC38 tumour; Rapamycin: myeloid and cancer cells’s FDG uptake↓ (significant)
F - H	MC38 tumours Rapamycin: myeloid cell metabolism　ex vivo↓　 cancer cells and T cells remained unchanged
I	Untreated tumours: CPA and unbiased clustering based only on (metabolism-related transcripts) grouped samples by cell identity (RNA-Seq)
J, K	Rapamycin: (flow cytometry) HK1↓ across tumour cell populations HK2↓ specifically in TAMs potentially underlying the differences between tumour cell types in glucose uptake
L, M	Rapamycin: GLUT1: unchanged; protein levels of the iron transporter CD71 and the amino acid transporter CD98 ↓