Reza/Raja quiz 10

Question 1

___: it is a characteristic of nutrient competition, low ph, limited oxygen and accumulation of metabolites
-such conditions result in immunosuppressive or tolergenic phenotypes of immune cells that encourage metabolism to rely on _____and ____

Answer 1

1. tumor microenvironment
   2.oxidative phosphorylation and fatty oxidation

Question 2

tumor microenvironment accelerate T effector cell exhaustion and increase immune checkpoint expression, this promotes differentiation and accumulation of ____

Answer 2

Treg, M2-like macrophages and myeloid-derived dendritic cells (MDSC)

Question 3

tumor microenvironement also produces unique subsets of myeloid cells known as _____and ____

Answer 3

tumor associated dendritic cells (TADCs) and tumor associated neutrophils (TANS)

Question 4

tumor microenvironment nutrient deprivation includes?

Answer 4

decrease glucose, decrease glutamine, decrease arginine

Question 5

tumor microenvironment metabolite accumulation includes?

Answer 5

increase lactate and increase kynurenine

Question 6

tumor microenvironment includes ____ and ____

Answer 6

acidity and hypoxia

Question 7

activated T cells: lead to an increase in glycolytic and glutaminolytic metabolism by using ___ for ATP production and biosynthesis for clonal expansion

Answer 7

aerobic glycolysis

Question 8

regulatory T cells (Tregs) rely on ___ and ___ to support their survival and differentiation

Answer 8

oxphosphorylation and fatty oxidation

Question 9

macrophages reprogram their metabolism in response to tumor microenvironment through ____ while maintaining function of cytokine production

Answer 9

glycolysis, fatty acid synthase and altered nitrogen cycle metabolism

Question 10

tumor associated macrophages (TAM) are categorized into ___ and __ phenotypes

Answer 10

M1 like and M2 like

Question 11

____: increase inflammatory phenotype, use glycolysis, fatty acid synthase and amino acid metabolism

Answer 11

M1 like

Question 12

___: have suppressive phenotype, using fatty acid oxidation and TCA cycle

Answer 12

M2 like

Question 13

neutrophils normally are purely glycolytic to support ___and __-

Answer 13

ATP generation and microbial killing

Question 14

neutrophils in cancer it is considered glucose restricted conditions, neutrophils engage in oxidative mitochondrial metabolism and fatty acid oxidation to support NADPH oxidase dependent ___

Answer 14

ROS production

Question 15

the increase in glycolytic activity of cancer cells combined with poor vascular exchange results in: ____

Answer 15

-decrease glucose in TME
-limit in T cell expansion
-decrease in effector function through competition or altered apoptosis or eventual exhaustion

Question 16

immune checkpoint blockade is an immune targeted strategy used clinically for cancer, an increase in expression of checkpoint receptors is due to ____ in TME, engagement of receptors decrease glycolysis and increase fatty acid oxidation

Answer 16

low glucose, acidity or lactate

Question 17

antibodies against immune checkpoint bloackade receptors restores?

Answer 17

glycolysis

Question 18

most promising therapy: immune checkpoint blockade (ICB) restores ____ metabolism and effector function in TILs

Answer 18

anabolic

Question 19

accumulation of lactate in TME promote immunosuppressive immune cells through m2 macrophage polarization, MDSC infiltration, Treg survival and inhibiting T effector functions
-decreasing lactate: by inhibiting ___or neutralizing ____
-checkpoint receptor VISTA: using ___exploits TME to imrpove treatment specificity. targeting this can be TME-context and immune cell specific so anticancer effects still unclear

Answer 19

1. lactate producing enzyme LDH, inhibiting lactate transporters MCT1/4 or neutralizing lactic acid induced acidity
2. acidic PH selective antibody

Question 20

increase in glycolytic activity of cancer cells under hypoxic condition ____which acidifies TME

Answer 20

increase lactate build up

Question 21

____: LDH is correlated with tumor size and clinical severity

Answer 21

LDH

Question 22

lactic acid inhibit effector T cell function through decrease proliferation by inhibiting monocyte activation and dendritic cell differentiation it promotes m2 polarization through ____
-lactic acid can also boost Treg survival in TME, due to Tregs ability to oxidize exogenous lactate

Answer 22

increase arginase and HIF-1alpha stabilization

Question 23

___: inhibits natural killer cells function and increase MDSCs contributing to suppressive microenviornment

Answer 23

lactate

Question 24

___: relieas on nitric oxide synthetase (NOS) and arginase (ARG) enzyme

Answer 24

arginine metabolism

Question 25

what role does tryptophan play in TME? cancer cells alter the chemical composition of the extracellular milieu, this exerts ____on the phenotypes of normal cells in the tumor extracellular matrix -the microenvironment affects metabolism and signaling responses of cancer cells

Answer 25

pleiotropic effects

Question 26

glutamine metabolism is altered as a result of TME inhibiting glutaminolysis through blocking ____, this promotes a pro-inflammatory macrophage phenotype

Answer 26

glutaminase (GLS)

Question 27

therapies that facilitate metabolism of arginine through iNOS cor cancer therapy; macrophages using iNOS have ___phenotype. their NO secretion promotes T cell extravasion and homing against tumors -macrophage derived NO results in ___which is important for T cell extravastation

Answer 27

1.M1 like 2. decrease VCAM-1

Question 28

tregs, tolergenic DCs and MDSCs have increased expresion of ___

Answer 28

indoleamine 2,3 dioxygenase (IDO)

Question 29

why is IDO important?

Answer 29

its the enzyme responsible for metabolizing tryptophan to kynurenine

Question 30

targeting IDO suppress the immune subsets reducing ___in the microenviornment

Answer 30

kynurenine

Question 31

T cell infiltration into tumor from blood involves? -through these t cell is able to go through cell junctions of blood vessels into tissue along chemokines making vascular cell adhesion molecule (VCAM-1)

Answer 31

1. selectins and their ligands 2. chemokines and their receptors 3. integrins and their ligands

Question 32

hypoxia mediated events limit the energy supply by reducing ___lvels in TME with ___. this occurs by breakdown of ATP by ectonucleotidases CD39 and CD37

Answer 32

decrease ATP, increase of adenosine

Question 33

___: hydrolyzes ATP to ADP and AMP

Answer 33

CD39

Question 34

____: catabolize extracellular AMP, converting it to adenosine

Answer 34

CD73

Question 35

engagement of extracellular adenosine and A2AR receptors on surface of T cells, NK cells, macrophages/dendritic cells and neutrophils leads to long lasting tumor growth makes good target for cancer therapy -blockade of ___: maintain ATP in TME by preventing its degradation -Blockade of ___: block adenosine generation -Blockade of ____: block the activity of adenosine

Answer 35

1. blockade CD39 2. Blockade of CD73 3. Blockade of A2AR

Question 36

____; is essential for T cell proliferation, serving as a precursor for protein and lipid biosynthesis

Answer 36

glutamine

Question 37

____: glutamine enters through several plasma membrane glutamine transporter and is used in the cytosol in biosynthesis of nucleotides, asparagnine and UDP-GLcNAC

Answer 37

glutamine metabolic pathways

Question 38

glutamine derived alpha ketoglutarate supplies metabolite for TCA cycle and fuels the generation of 2-HG under conditions of ____or ____

Answer 38

IDH2 mutation or hypoxia

Question 39

_____via reductive carboxylation supports fatty acid synthesis under hypoxia or HIF-2a transcription factor stabilization

Answer 39

citrate derived from glutamine

Question 40

glutamine is catabolized into glutamate by glutaminase (GLS) then internalized into mitochondria and converted to alpha ketogluterate and then entering/fueling TCA cycle -alternate pathway for fatty acid synthesis is reductive carboxylation which involves carbon produced by glutamine metabolism; glutamine derived alpha ketoglutarate is reduced by the consumption of ___ in the reverse reaction to form citrate

Answer 40

NaDPH by isocitrate dehydrogenase (IDH)

Question 41

glutamine has an essential role in ATP production, de novo synthesis of nucleotides (DNA and RNA) and production of macromolecules; glutaminase potential target for cancer therapy (glutaminase inhibitors) for _____

Answer 41

solid tumors

Question 42

___: is a mitochondrial enzyme that catalyzes oxidative decarboxylation of isocitrate to alphaketoglutarate

Answer 42

IDH2

Question 43

____: conversion of alpha ketogluterate to D-2 hydroxyglutarate (2HG); result in excess 2HG a competitive inhibitor needed for demethylation of cytosine nucleotides in DNA

Answer 43

IDH2 mutations

Question 44

increase fatty acids in TME result in ___in immune cells or promote FAO -immune suppressive phenotypes rely on FAO to produce energy

Answer 44

increase lipid droplets

Question 45

targeting ___ or ___ is an area for cancer therapy

Answer 45

FASN or ACC

Question 46

____: is a facilitator of FA transport in tissues with a high capacity for fatty acid metabolism

Answer 46

CD36