Viral status, immune microenvironment and immunological response to checkpoint inhibitors in hepatocellular carcinoma

Abstract

Background and aimsImmune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have clinical activity in hepatocellular carcinoma (HCC), but only a subset of patients respond to these therapies, highlighting a need for novel biomarkers to improve clinical benefit. HCC usually occurs in the setting of liver cirrhosis from chronic hepatitis B or C viral infection, but the effects of viral status on the tumor immune microenvironment and clinical responses to ICIs in HCC remains unclear.MethodsWe conducted a meta-analysis to estimate the objective response rates for PD-1/PD-L1 inhibitors in virally-infected and uninfected patients, and examined the effects of viral etiology on the tumor microenvironment using data from The Cancer Genome Atlas, as well as peripheral blood responses using an independent cohort of patients studied by mass cytometry (cytometry by time-of-flight (CyTOF)).ResultsMeta-analysis comparing objective response rates (ORR) between virally-infected and uninfected patients showed no clinically meaningful difference (absolute difference of ORR in virally-infected vs uninfected=−1.4%, 95% CI: −13.5% to 10.6%). There was no relationship between viral etiology on features of the tumor immune microenvironment that are known to modulate responses to PD-1/PD-L1 inhibitors, and the tumor mutational burden was similar between virally-infected and uninfected HCC. RNA sequencing of tissue-resident T cell and B cell repertoires similarly showed no effect of viral status on their diversity. CyTOF analysis of peripheral blood specimens further demonstrated similar expression of immune-related markers in response to PD-1 inhibitor therapy in virally-infected and uninfected HCC.ConclusionThere is no significant effect of viral etiology on the tumor immune microenvironment in HCC, and viral status should not be used as a criterion to select patients for PD-1/PD-L1 therapy.

<p>Baseline HBV Loads Do Not Affect the Prognosis of Patients with Hepatocellular Carcinoma Receiving Anti-Programmed Cell Death-1 Immunotherapy</p>

“…The antitumor ability of ICIs may depend on other carcinogenetic processes rather than on HBV-related cascades. 31 Ho et al have found that viral etiology has no effect on the tumor immune microenvironment, and viral status should not be adopted as a criterion for ICI medication. 31 Since viral status had no impact on the efficacy of ICIs, it can be inferred that viral load may not compromise the efficacy of anti-PD-1 blockade, which was supported by our data.…”

Current therapeutic options for gastric adenocarcinoma

“…In hepatocellular carcinoma (HCC), PD-1(programmed cell death protein-1)/PD-L1 (programmed death ligand-1) pathways have been inhibited by immune checkpoint inhibitors (ICIs). However, only a small group of GC patients supported these therapeutic techniques, indicating the need for significant biomarkers identification to enhance clinical benefits ( Ho et al, 2020 ). Arresting the communication between PD‐1 protein with its ligands such as PD‐L1, and PD‐L2 may lead to an effective antitumor response and improve clinical outcomes in patients ( Ishikawa et al, 2018 ) (see Fig.…”

Interaction between hepatitis B virus infection and the efficacy of camrelizumab in combination with apatinib therapy in patients with hepatocellular carcinoma: a multicenter retrospective cohort study

“…The present study provided evidence that baseline HBV DNA load does not affect the tumor response of anti-PD-1 + antiangiogenesis therapy by constructing a retrospective cohort that included HCC patients who received C+A therapy. HBV infection may have no effect on TMEs, as it might integrate into both hepatocytes and tumor cells, and as a result, the anti-tumor ability of anti-PD-1 might not depend on HBV-associated immune attacks but on other carcinogenetic processes (22).…”