ALDH2 polymorphism rs671 is a predictor of PD-1/PD-L1 inhibitor efficacy against thoracic malignancies

Abstract

Background: Aldehyde dehydrogenase 2 (ALDH2) plays an important role in the endogenous aldehyde detoxification of various types of cells. ALDH2*2, a variant allele of the ALDH2 polymorphism rs671, leads to decreased enzymatic activity. ALDH2*2 may enhance tumor antigen presentation due to aldehyde-induced DNA damage while suppressing peripheral blood T cell counts and T cell activation.

Methods: On the basis of our hypothesis that rs671 affects the sensitivity of immune checkpoint inhibitors (ICIs), we evaluated the effects of rs671 on patients with thoracic malignancies who started ICI therapy in 2016-2019. The cohort consisted of 105 cases, including 64 cases with adenocarcinoma and 30 cases with squamous cell carcinoma, 49 of whom were ALDH2*2 carriers. The first ICI was PD-1/PD-L1 inhibitor (Nivolumab, Pembrolizumab, or Atezolizumab) in all cases.

Results: The best response to anti-PD-1/PD-L1 therapy (partial response/stable disease/progressive disease) was 36%/50%/14% in the rs671(-) cases; however, the response was relatively poor in the rs671(+) cases (27%/29%/45%, respectively) (p = 0.002). The hazard ratio (95% confidence interval) of disease progression within the observation period of 6 months for the rs671(+) cases was estimated to be 5.0 (2.5-10) after the adjustment for covariates, including sex, Brinkman index, treatment line, tumor tissue programmed death-ligand 1 positivity rate, tumor tissue EGFR mutation. This association was also maintained in a stratified analysis, suggesting that ALDH2*2 is an independent negative predictive factor for the short-term prognosis of anti-PD-1/PD-L1 therapy. Thus, the progression-free survival (PFS) ratio of the rs671(+) cases decreased rapidly after ICI initiation but was eventually higher than that of the rs671(-) cases (restricted mean survival time in 12 months from 2 to 3 years afterward was 1.3 times that of the rs671(-) cases). Moreover, the highest PFS ratio after 2 years among sub-groups was found in the first-line treatment sub-group of rs671(+) group (40%).

Conclusions: Our study suggests that rs671 may be an accurate and cost-effective predictor of PD-1/PD-L1 inhibitor treatment, in which optimal case selection is an important issue.

Keywords: ALDH2; Immune checkpoint inhibitors; Thoracic malignancy; rs671.

Fig. 1

Progression-free survival after the initiation of PD-1/PDL-1 inhibitor therapy. Kaplan–Meier plots were shown for patients with a thoracic malignancy. ICI, immune checkpoint inhibitor; Rs671(−), ALDH2*1/*1 (n = 56), rs671(+); ALDH2*1/*2 or ALDH2*2/*2 (n = 49). p, p value for Gahan–Breslow–Wilcoxon test

Fig. 2

Progression-free survival after the initiation of immune checkpoint inhibitor therapy by ALDH2 rs671 polymorphism. Kaplan–Meier plots were shown for patients with thoracic malignancies. ICI; immune checkpoint inhibitor, Rs671(−); ALDH2*1/*1, rs671(+); ALDH2*1/*2 or ALDH2*2/*2. p, p value for Gahan–Breslow–Wilcoxon test

Fig. 3

Stratified hazard ratio of cancer progression for ALDH2*2 carriers estimated from a 6-month observation. Reference = ALDH2*1/*1 carriers. Hazard ratio and 95% confidence interval (error bar) were estimated by Cox proportional hazard model adjusted for covariates used in Model 4 in Table 4. PD-L1; programmed death-ligand 1, EGFR; epidermal growth factor receptor. Cases with unknown TNM classification (N = 29), unknown PD-L1 (+) ratio in cancer tissue (N = 15), and unknown EGFR mutation in cancer tissue (N = 16) were excluded

Fig. 4

Hazard ratio of cancer progression by ALDH2 genotype estimated from the entire observation period. Rs671(−); ALDH2*1/*1, rs671(+); ALDH2*1/*2 or ALDH2*2/*2. Hazard ratio and 95% confidence interval (error bar) was estimated by the Cox proportional hazard model includes all explanatory covariates shown in this figure. ICI; immune checkpoint inhibitor, PD-L1; programmed death-ligand 1, EGFR; epidermal growth factor receptor, p-value for interactions was estimated by the model including all covariates shown above, rs671, and interaction in terms of sex*rs671, type of ICI*rs671, treatment line*rs671, PD-L1 ratio*rs671, and EGFR mutation*rs671. P values are shown separately for each genotype with forest plot if p < 0.2. All p values for interaction are shown on the right