insight - Oncology - # Telomere Influence on TNBC Immune Response

Telomere Length and IL1 Signaling in TNBC Immune Suppression

Q: How does telomerase activity impact telomere length regulation?

Telomerase is the enzyme responsible for maintaining and elongating telomeres by adding repetitive nucleotide sequences to the ends of chromosomes. In normal somatic cells, telomerase activity is typically low or absent, leading to gradual shortening of telomeres with each cell division. This process eventually triggers cellular senescence or apoptosis as a protective mechanism against uncontrolled cell proliferation. In cancer cells, however, reactivation of telomerase allows for continuous maintenance and even elongation of telomeres, enabling immortalization and sustained growth. Telomerase activity impacts telomere length regulation by counteracting the natural shortening that occurs during DNA replication in rapidly dividing cancer cells. This leads to the preservation of chromosomal integrity and promotes tumor progression.

Q: Could alternative mechanisms besides TERC contribute to telomere length variation?

While TERC (telomerase RNA component) plays a crucial role in providing the template for synthesizing new telomeric repeats by the catalytic subunit TERT (telomerase reverse transcriptase), there are alternative mechanisms that can also influence telomerelength variation: ALT Mechanism: Some cancer cells utilize an alternative lengthening of telomers (ALT) mechanism instead of relying on traditional telomerelengthening through TERT/TERC-mediated pathways. ALT involves homologous recombination-based processes that result in heterogeneous lengths at chromosome ends. Shelterin Complex Dysfunction: Disruption in components of the shelterin complex, which protects and regulates teleromes' structure, can lead to abnormal variations intelomerlengths. DNA Damage Response Pathways: Activationof DNA damage response pathways due to various stressors can affecttelomehomeostasisand contribute totelorlelengthvariationby influencing repairmechanismsatchromosomeends. Epigenetic Modifications: Changes in epigenetic marks near teleres may alter their accessibilitytoTELORASEor other factors involvedintelorlenghregulationleadingtoteloerlengthvariations These alternate mechanisms highlightthe complexityofteloregulationandthepotentialforvariousfactorsbeyondTECRtoplayaroleintelolengthvariationincancerandothercellularcontexts.

Q: What implications do the findings have for potential targeted therapies against TAM infiltration?

The findings suggesting a link between IL1R1 expression,telomore-length,andTAM infiltrationhave significantimplicationsfortargetedtherapiesagainstTAMsinTNBC.Theseimplicationsinclude: 1.TherapeuticTargetingofIL-1Signalling:SinceIL-1signalingislinkedtoNF-kappaBactivationandsubsequentcytokineexpressionthatpromotesM2-likeTAMphenotype,targetingthispathwaycouldbeaneffectivestrategytoreducetumor-promotingimmunosuppressiveeffectsassociatedwithTAMs.Targetedtherapies,suchasIL-RAorIL-Rantagonists,couldbedevelopedtoinhibittheinteractionbetweenIL-1andreceptorslikeIL-R1,reducingM2macrophageinfiltrationinthetumormicroenvironment. 2.Telomore-LengthModulation:Treatmentsthatmodulateteloreregulationmayalsobeexploredastherapeuticstrategiestoalterimmuneresponseswithinthetumormicroenvironment.InhibitingTRF2-dependentactivationofIL-IRIthroughmanipulatingteloerlength-sensitivepathwayscouldpotentiallyimpactTAMrecruitmentandinflammatorycytokineproduction.Thisapproachmightofferanovelwaytosuppressimmunosuppressiveelementsintumorstoenhanceanti-tumorimmunity 3.PersonalizedTherapyApproaches:Consideringthedifferencesintelome-lengthsandtheirassociationwithimmune-modulatorypathways,TNBCpatients'maybenefitfrompersonalizedtherapytargetingthespecificmolecularmechanismsidentifiedinthestudy.PatientsshowingshorterteloreresultinginalteredcytokineexpressionandsignificantTAMinfiltrationmaybegoodcandidatesfortreatmentsaimedattargetingteloermaintenanceorthecytokinesignalingaxisassociatedwithTL-sensitivemechanisms Byleveragingtheseinsights,intonewpotentialtherapeuticavenuescanbedevelopedinTNBCmanagementfocusedontargetingtam-infltrationandanitsubsequentpro-tumorigeniceffects

Core Concepts

Telomere length affects IL1 signaling, modulating immune response in TNBC.

Abstract

Telomeres play a crucial role in cancer progression, impacting immune signaling and tumor microenvironment. Telomere length influences TRF2 binding at the IL1R1 promoter, affecting NF-kappaB activation and cytokine expression. Telomere-sensitive IL1 signaling correlates with TAM infiltration in TNBC, highlighting the role of telomeres in modulating tumor immunity.

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biorxiv.org

Stats

Telomerase activity negatively correlated with telomere length in TNBC.
TERC was significantly enhanced in TNBC-LT samples.
70% of TNBC samples showed lower telomere length in tumors compared to adjacent normal tissue.
EpCAM+ve cells exhibited significant TL heterogeneity between TNBC-ST and LT samples.
IL1R1, IL1B, TNF, and IL3 were lower in long telomere TNBC samples.

Quotes

"Enhanced TRF2 binding at the IL1R1 promoter directly recruits p300 for H3K27 acetylation."
"TRF2-K293R mutation compromised activation of IL1R1 due to reduced p300 recruitment."
"IL1 signaling through NF-kappaB activation is specifically regulated by TRF2."

Key Insights Distilled From

Telomere length sensitive regulation of Interleukin Receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment

by Mukherjee,A.... at www.biorxiv.org 12-08-2021

https://www.biorxiv.org/content/10.1101/2021.12.07.471419v5

Deeper Inquiries

How does telomerase activity impact telomere length regulation?

Telomerase is the enzyme responsible for maintaining and elongating telomeres by adding repetitive nucleotide sequences to the ends of chromosomes. In normal somatic cells, telomerase activity is typically low or absent, leading to gradual shortening of telomeres with each cell division. This process eventually triggers cellular senescence or apoptosis as a protective mechanism against uncontrolled cell proliferation.
In cancer cells, however, reactivation of telomerase allows for continuous maintenance and even elongation of telomeres, enabling immortalization and sustained growth. Telomerase activity impacts telomere length regulation by counteracting the natural shortening that occurs during DNA replication in rapidly dividing cancer cells. This leads to the preservation of chromosomal integrity and promotes tumor progression.

Could alternative mechanisms besides TERC contribute to telomere length variation?

While TERC (telomerase RNA component) plays a crucial role in providing the template for synthesizing new telomeric repeats by the catalytic subunit TERT (telomerase reverse transcriptase), there are alternative mechanisms that can also influence telomerelength variation:

ALT Mechanism: Some cancer cells utilize an alternative lengthening of telomers (ALT) mechanism instead of relying on traditional telomerelengthening through TERT/TERC-mediated pathways. ALT involves homologous recombination-based processes that result in heterogeneous lengths at chromosome ends.

Shelterin Complex Dysfunction: Disruption in components of the shelterin complex, which protects and regulates teleromes' structure, can lead to abnormal variations intelomerlengths.

DNA Damage Response Pathways: Activationof DNA damage response pathways due to various stressors can affecttelomehomeostasisand contribute totelorlelengthvariationby influencing repairmechanismsatchromosomeends.

Epigenetic Modifications: Changes in epigenetic marks near teleres may alter their accessibilitytoTELORASEor other factors involvedintelorlenghregulationleadingtoteloerlengthvariations

These alternate mechanisms highlightthe complexityofteloregulationandthepotentialforvariousfactorsbeyondTECRtoplayaroleintelolengthvariationincancerandothercellularcontexts.

What implications do the findings have for potential targeted therapies against TAM infiltration?

The findings suggesting a link between IL1R1 expression,telomore-length,andTAM infiltrationhave significantimplicationsfortargetedtherapiesagainstTAMsinTNBC.Theseimplicationsinclude:
1.TherapeuticTargetingofIL-1Signalling:SinceIL-1signalingislinkedtoNF-kappaBactivationandsubsequentcytokineexpressionthatpromotesM2-likeTAMphenotype,targetingthispathwaycouldbeaneffectivestrategytoreducetumor-promotingimmunosuppressiveeffectsassociatedwithTAMs.Targetedtherapies,suchasIL-RAorIL-Rantagonists,couldbedevelopedtoinhibittheinteractionbetweenIL-1andreceptorslikeIL-R1,reducingM2macrophageinfiltrationinthetumormicroenvironment.
2.Telomore-LengthModulation:Treatmentsthatmodulateteloreregulationmayalsobeexploredastherapeuticstrategiestoalterimmuneresponseswithinthetumormicroenvironment.InhibitingTRF2-dependentactivationofIL-IRIthroughmanipulatingteloerlength-sensitivepathwayscouldpotentiallyimpactTAMrecruitmentandinflammatorycytokineproduction.Thisapproachmightofferanovelwaytosuppressimmunosuppressiveelementsintumorstoenhanceanti-tumorimmunity
3.PersonalizedTherapyApproaches:Consideringthedifferencesintelome-lengthsandtheirassociationwithimmune-modulatorypathways,TNBCpatients'maybenefitfrompersonalizedtherapytargetingthespecificmolecularmechanismsidentifiedinthestudy.PatientsshowingshorterteloreresultinginalteredcytokineexpressionandsignificantTAMinfiltrationmaybegoodcandidatesfortreatmentsaimedattargetingteloermaintenanceorthecytokinesignalingaxisassociatedwithTL-sensitivemechanisms
Byleveragingtheseinsights,intonewpotentialtherapeuticavenuescanbedevelopedinTNBCmanagementfocusedontargetingtam-infltrationandanitsubsequentpro-tumorigeniceffects