tumor microenvironment analysis provides insights into the … · 2019. 2. 12. · priyadharshini ,...

Key findingsv OncoPeptTUME identifies cancers in which CD8 T-cell infiltration differentially affects

patient survivalv Differentially expressed genes in these two groups identify pathways that interact

with CD8 T-cells to impact outcomev Poor prognosis group shows enrichment of ECM and immunosuppressive pathways

absent from the good prognosis group

Tumor microenvironment analysis provides insights into the activity of CD8 T-cells and their impact on survivalAshwiniPatil,MS1,NitinMandloi,MS1,KiranV.Paul,MS1,MaliniManoharan,PhD1,PriyankaShah,PhD1, Sushri

Priyadharshini ,MS1, Rohit Gupta,PhD1,andAmitabha Chaudhuri,PhD1,RaviGupta,PhD1,1MedGenomeInc,Fostercity,California,UnitedStates

• The TCGA data was analyzed using MedGenome’sproprietary OncoPeptTUME solution. The solutionemploys curated gene expression signatures todissect components of the tumor microenvironment.The abundance of cells in the tumors is calculatedfrom the expression of genes contained in eachsignature.

• www.medgenome.com/oncopept

Methods

The tumor microenvironment regulates the behavior ofmalignant cells through a variety of heterotypic cell-cell and cell-matrix interactions. Tumor growth ispromoted by the failure of the immune-surveillancemechanisms to keep the tumor growth in check, andis further augmented by soluble factors produced bythe stromal cells, including the immune cells. In thisstudy, we analyzed TCGA data to investigate theimpact of CD8 T-cell infiltration on the diseaseoutcome. Our analysis indicates that CD8 T-cellinfiltration predicts favorable survival in certaincancers, whereas in other cancers survival wasunaffected. By comparing tumors from these twogroups, we show that multiple cell-intrinsic andextrinsic pathways modulate the anti-tumorigeniceffects of CD8 T-cells. The group favored by CD8 T-cell infiltration lacked extracellular matrix remodelingand other immune suppressive pathways that wereboth enriched in tumors lacking benefit of CD8 T-cellinfiltration.

1. Investigate the tumor microenvironment featuresusing the OncoPeptTUME solution.

2. Evaluate infiltration of CD8 T-cells in 9345 TCGAtumor samples from 33 cancers.

3. Analyze cell-intrinsic and extrinsic mechanisms thatimpact survival in the presence of CD8 T-cells.

Introduction Results

Figure 5. Expression checkpoint regulators

Figure 3. CD8 T-cell infiltration in 33 cancers

Figure 2. Creation of gene signatures

Figure 6. CD8 infiltration and survival outcome

Figure 4. Infiltration of CD8 T-cells and immune reactivity of the tumors.

Figure 7. Stromal, Immune and Epithelial content

ObjectivesFigure 8. Enrichment of PIK3CA mutations in Low CD8 tumors from breast cancer

Figure 1. OncoPeptTUME workflow

Conclusions

• Analysis of the CD8 T-cell content in 9345tumors from 33 cancers indicate that T-cellinfiltration varies significantly across tumors:35% in melanoma and 1% in prostate cancer.

• High T-cell infiltrated tumors are rich in T-cell-specific markers and IFN-gexpression althoughsurvival benefit is not seen in all cancers

• Activation of multiple oncogenic and tumorsuppressive pathways correlate with CD8 T-cellexclusion opening up opportunities for targetdiscovery.

• Our study identifies multiple pathways that canbe targeted to increase the sensitivity of tumorsto checkpoint blockade.

SurvivalBenefit

NoBenefit

SKCM LUAD

BRCA LUSC

HNSC THCA

CESC LIHC

KIRC

STAD

Breastcancer

HighCD8(12%mutatedsamples)

LowCD8(23%mutatedsamples)

CD8Score

CD8Score

StromalImmuneEpithelial

Timeindays

Survivalproba

bility

Survivalproba

bility SKCM

LUAD

P=0.0012

P=0.5

SKCM HNSC PRAD

HighmutationburdenMutationperMB>0.05

MediummutationburdenMutationperMB>0.01&<0.05

LowmutationburdenMutationperMB<0.01

35% 17% 1%

log2(R

SEM+1)