Paper - Review

DOI: 10.1038/s41586-021-03362-0

Abstract

HCC
← hepatocellular carcinoma
→ can have 1⃣ viral 2⃣ non-viral causes

NASH
← non-alcoholic steatohepatis
→ an important driver ← of HCC

Immunotherapy
→ has been approved → for treating HCC
Biomarker-based stratification of patients
← for optimal response to therapy
→ is an unmet need

❗: report → the progressive accumulation
← of 1⃣ exhausted 2⃣ unconventionally activated CD8+ PD1+ T-cells
← in NASH-affected livers

Therapeutic immunotherapy
← targeted at programmed death-1 (PD1)
→ expanded activated CD8+ PD1+ T-cells ← within tumors
→ did NOT ❌ lead → to tumor regression
∴ Tumor immune surveillance → was impaired

Anti-PD1 treatment
→ lead → to an increase ↑
← 1⃣ in the incidence of NASH-HCC 2⃣ in the number & size of tumor nodules
← which correlated ← with increased hepatic 1⃣ CD8+ PD1+ CXCR6+ 2⃣ TOX+ 3⃣ TNF+ T-cells

The increased
← in HCC triggered ← by anti-PD1 treatment
→ was prevented ←by depletion of 1⃣ CD8+ T-cells 2⃣ TNF neutralization
∴ Cd8+ T-cells → help to induce NASH-HCC
← rather than 1⃣ invigorating 2⃣ executing immune surveillance

Fount → similar phenotypic & functional profiles
← in hepatic CD8+ PD1+ T-cells ← from humans with 1⃣ NAFLD 2⃣ NASH

A meta-analysis of three randomized phase III clinical trials
→ that tested inhibitors of PDL1 & PD1
← in more than 1.6K patients ←with advanced HCC
∴ Immune therapy → did NOT ❌ improve survival
← in patients with non-viral HCC

Patients
← with NASH-driven HCC
← who received anti-PD1 & anti-PDL1 treatment
→ showed reduced overall survival
← compared to patients ←with other aetiologies

Non-viral HCC
← particularly NASH-HCC
→ might be less responsive → to immunotherapy
∵ NASH-related aberrant T-cell activation → causing tissue damage
∴ leads → to impaired immune surveillance

❗: A rationale → for stratification of patients
← with HCC according to underlying aetiology
→ in studies of immunotherapy ← as a primary & adjuvant treatment

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