Background
Aldehyde dehydrogenase 2 (ALDH2) is expressed in many tissues, including blood cells [
1,
2], and metabolizes endogenous aldehydes, such as formaldehyde, acetaldehyde, and 4 hydroxynonenal (4HNE) [
3,
4]. Approximately half of the Japanese population and at least 2% of the global population shows the low-activity phenotype derived from the
ALDH2 genetic polymorphism rs671 (the variant allele is named
ALDH2*2), which is associated with differences in lifestyle habits, disease risks, and drug sensitivities [
5,
6]. The association is complicated, bidirectional, and rather strong [
7]. For example, esophageal cancer is less common among
ALDH2*2 carriers due to reduced drinking habits, but
ALDH2*2 carriers with drinking habits show the highest risk because of accumulated aldehydes [
8]. Additionally,
ALDH2*2 is reported to increase the risk for leprosy [
9], whereas viral hepatitis is mild in
ALDH2*2 carriers [
10], likely due to the alleviation of inflammation by the presence of aldehydes [
11,
12]. Because hepatitis is a primary carcinogenesis promoter, it is reasonable that
ALDH2*2 is reported as a protective factor against liver cancer [
13,
14].
Immune checkpoint inhibitors (ICIs) are an innovative cancer treatment that provides benefits for some but not the majority of patients; therefore, understanding the ICI-sensitive population is an important challenge. To date, rs671 has not been studied as a potential predictor of ICI treatment, but it may have a complicated, bidirectional, and strong effect on ICI therapy for the following reasons: 1) Cancer cells of
ALDH2*2 carriers may show more DNA damage induced by aldehyde exposure during smoking and drinking [
15,
16], resulting in an increased presentation of antigens to immune cells, which is advantageous in ICI treatment. 2) Because endogenous 4HNE, a typical endogenous aldehyde that accumulates in
ALDH2*2 carriers, delays cell proliferation [
3,
17‐
20], ICI resistance due to genetic mutations in cancer cells [
21,
22] is less likely to occur. 3) However, high aldehyde concentrations can suppress immune cell activation [
12], making the short-term effect of ICIs difficult to detect. 4) Nevertheless, T cell exhaustion is unlikely to occur [
23,
24], and this may be advantageous in long-term ICI therapy. 5) Lastly, the low T cell count in the peripheral blood of
ALDH2*2 carriers reported previously may have a negative effect on ICI treatment [
25]. Thus, to verify the hypothesis that
ALDH2*2 carriers show a different ICI sensitivity compared with non-carriers, we investigated patients with ICI-treated thoracic malignancies.
Discussion
As expected, the
ALDH2 polymorphism rs671 influenced the effects of anti-PD-1/PD-L1 therapy on thoracic malignancies.
ALDH2*2 had a negative effect on short-term prognosis, although it was unlikely to affect long-term prognosis. According to multivariable and stratified analyses, the negative effect was independent of sex, smoking habit, PD-L1 expression rate, and
EGFR mutation. Compared with
EGFR mutation, which has been shown to be associated with poor prognosis independent of ICI or initial ICI efficacy [
30,
36], rs671 may be more strongly associated with initial ICI efficacy. However,
ALDH2*2 showed no negative effect on long-term survivors, especially the first treatment line group; thus, we found that
ALDH2*2 is not consistently associated with negative effects.
Several findings that support the negative impact of
ALDH2*2 on the short-term prognosis of ICI therapy have been reported. Gao et al. (2018) showed that drug-induced T-cell hepatitis is suppressed by exogenous acetaldehyde. Mechanistically, aldehyde suppresses the secretion of cytokines by inhibiting the phosphatidylinositol 3-kinase (PI3K)-Akt pathway in T cells or promotes the secretion of glucocorticoids that suppresses the activation of T cells [
12]. This suppression of the PI3K-Akt pathway has also been confirmed in the cardiomyocytes of
Aldh2−/− mice, in which endogenous aldehydes accumulate in the absence of exogenous aldehyde [
37]. These findings suggest that endogenous aldehyde also suppresses the PI3K-Akt pathway in T cells. The PI3K-Akt pathway is important for T cell differentiation [
38] and has been shown to decrease the number of T cells in the thymus gland when activity is impaired [
39,
40]. In fact, we found that the number of T cells in the peripheral blood of untreated
Aldh2−/− mice and healthy
ALDH2*2 carriers is low [
25]. On the basis of these findings, we hypothesize that
ALDH2*2 negatively affects the initial ICI efficacy via suppression of the PI3K-Akt pathway in T cells due to endogenous aldehyde accumulation.
Contrary to our previous finding [
25], the baseline lymphocyte counts in patients in the current cohort tended to be higher in the rs671(+) group (
p = 0.06, Table
1). Presumably, it is due to stronger antigen presentation of tumor cells, as mentioned above, associated with DNA damage due to higher aldehyde exposure than in the rs671(−) group. Baseline lymphocyte count is positively correlated with the efficacy of PD-1/PD-L1 therapy (
p = 0.02) (Table S
4), yet PFS in the first 6-month was worse in rs671(+) group than in rs671(−) group (Model 1—3, Table
4), and the finding became more obvious after adjustment of lymphocyte count (Model 4, Table
4). Thus, it is suggested that both T cell function and number are required for effective PD-1/PD-L1 therapy.
As explained above, endogenous aldehyde can also be advantageous. In the present study, the PFS ratio in the rs671(+) group decreased rapidly but was eventually higher than that of the rs671(−) group (0.21 vs. 0.27). For the first-line group, the PFS ratio after 2 years was 0.37 in the rs671(−) group and 0.40 in the rs671(+) group and was substantially higher compared with that in the other groups (the PFS ratio after 2 years was 0.18–0.23 in the rs671(−) and rs671(+) groups after the second-line treatment). Because treatment before ICI may have reduced lymphocyte in the rs671(+) group, based on general linear regression model to estimate association between log (lymphocyte count) and treatment line with adjustment for age and sex (p = 0.04), while no such effect was detected in rs671(−) group (p = 0.98), it is suggested that preventing a decrease in the number of T cells caused by pre-ICI treatment may increase the chances of obtaining a good ICI effect.
The response rate to ICIs is currently insufficient. For example, only 10–20% of patients with non-small-cell lung cancer (NSCLC) [
41,
42] respond to this therapy. Therefore, optimal case selection is important. The effects of ICI are affected by the immunity of the host, the intestinal bacterial environment of the host, and tumor tissue factors [
43,
44]. The PD-L1 expression level and
EGFR mutation rate, which are tumor tissue factors, are currently used as predictors in clinical settings. In the present study, there was no association between the PFS and PD-L1 ratio, possibly due to time width between tissue evaluation and the start of the ICI. However,
EGFR mutation was shown to be a negative predictor as previously reported, although only for rs671(−). It also has been shown that tissue infiltrating lymphocytes and tumor mutation burden can be predictors of treatment effects, although they have not been applied clinically [
44‐
46]. The most significant limitation of these factors is that highly invasive biopsies are required. Because the microenvironment and gene mutations of tumor cells are known to fluctuate dynamically, collecting tumor tissues immediately before treatment is ideal. However, this may often be difficult due to the condition of patients and the site of lesions. Meanwhile, Hatae et al. (2020) recently showed that blood metabolites reflecting the state of intestinal bacteria and tumor-specific T cell rates are good predictors of ICI effects on NSCLC, although there are still difficulties owing to the number of tested parameters after the start of treatment [
47]. Ohue et al. (2019) demonstrated that the effects of ICIs on NSCLC could be predicted by tumor antigens in blood samples collected prior to ICI initiation [HR (95% CI) of PFS in patients with antigen-positive is 0.4 (0.2 to 0.9)] [
48], and its clinical application is expected. Compared with these predictors, the analysis of
ALDH2 polymorphisms has some advantages: non-invasive, inexpensive, 100% determinable, and polymorphisms do not change throughout life.
The limitations of the present study are as follows: 1) The sample size was insufficient to establish prognostic factors specific to patients with rs671(+). 2) Because the present study was limited to Japanese patients with thoracic malignancies who were mostly men, it cannot be generalized to other types of cancers and populations. 3) Because several time-dependent covariates can affect the outcome, such as adverse reactions and types and doses of second and subsequent ICIs, controlling covariates is insufficient for long-term observation. 4) The biological mechanism is not well supported.
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