immunotherapy and predictive biomarkers · 2019-12-05 · immunotherapy and predictive biomarkers....
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Vasiliki SiozopoulouPathologistAntwerp University HospitalCORE – University of Antwerp
Immunotherapy and predictivebiomarkers
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Immunecheckpoint Inhibitory (ICI) therapy
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ICI therapy
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ICI therapy
Disadvantages of PD-L1 as a single-analyte biomarker
• Heterogeneity• Poor negative predictive value
• Relationship of PD-L1 to prognosis is controversial• Differs between tumor types
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ICI therapy
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ICI therapy
Important information for the pathologist
Indication and potential immunotherapeutic drug?
• Different clone (28-8, SP142, 22C3, SP263…)• Different scoring systems
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ICI therapy
• NSCLS
• TNBT
• UC (atezo)
(pembro)
• (HNSCC)
• (EC)
• 28-8
• SP142
• SP263
• 22C3
• TPS
• IC
• CPS
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ICI therapy
Scoring systems
TPS: Tumor Proportion Score (%)
IC: Tumor-infiltrating immune cell score (%)
CPS: Combined Positive Score (not a %)
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ICI therapy
Indication UC HNSCC Esophageal ca
Cutoff(s) < 10 𝑎𝑛𝑑 ≥ 10 < 1, ≥ 1 𝑎𝑛𝑑 ≥ 20 < 10 𝑎𝑛𝑑 ≥ 10
Scoring of tumor cells
Invasive carcinoma and high grade dysplasia / carcinoma in situ
Only invasive carcinoma cells
Invasive carcinoma including intramucosal adenocarcinoma
Scoring of immune cells
Tumor associated lymphocytes, histiocytes, macrophages
Ecxlude BCG granulom. Include giant cells Include giant cells
Scoring of other cell types
Excluded from scoring
Reported score CPS 0-100
Staining sample
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The tumor micro-environment (TME)
A: tumor cells B: immune celles
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The tumor micro-environment
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β – catenine pathway gives rise to a T cells exclusion phenotype
The tumor micro-environment – β-catenine
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• Patients with activation of β-catenine are very unlikely to benefit from ICI therapy
• Potential negative predictor
• Biomarker candidate
The tumor micro-environment – β-catenine
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The tumor micro-environment – β-catenine
DT:• Mesenchymal neoplasms • β-catenine mutation
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The tumor micro-environment
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Characterization of the tumor micro-environment:
• CD3/CD8/CD45Ro
• Exhausted phenotype?
• Regulatory cells?
The tumor micro-environment
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Antigen presentation
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Antigen presentation
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The role of INFγ
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The role of INFγ
Possible Mechanism Underlying the Controversial Effects of IFNγ in Tumor Immunity
• INFγ insensitivity / deletion signature (mutations of deletions of genes involved in the INF signaling pathway and antigen presentation)
• MHC downregulation and loss of immunogenicity
• Induction of IDO Tregs
• Expression of PD-L1
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Tumor Mutational Burden (TMB) and the role of Microsatellite Instability (MSI)
True neoantigen burden: the number of mutations actually targeted by T cells
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Tumor Mutational Burden (TMB)
Nat Rev Cancer. 2019 March ; 19(3): 133–150
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Tumor Mutational Burden (TMB)
Lowest mutational load• Low grade tumors • Pediatric malignancies (sarcomas)
Highly mutated• Environmental DNA damage
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Microsatellite Instability
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Microsatellite Instability
• MSI-positive tumor are specific type of high TMB tumor
• Generate numerous neopetpides hypermutated phenotype
• MSI is highly sensitive to ICI therapy regardless of the tissue of origin
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The Role of EGFR, non-immunogenic PD-L1 expression
• EGFR activation mutations can lead to overexpression of PD-L1 without neoantigen recognition
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Conclusions
• PDL1 IHC more or less retains its position as a predictive marker
• MSI: very interesting
• TMB: ?
• TME/TILs: interesting but not yet in practice
• Specific mutations as predictive biomarkers (β-catenine, EGFR, KRAS/STK11, PTEN…)
• Multicomponent predictive biomarker?