To the Editor,

Tumor mutation burden (TMB) is widely demonstrated to predict the efficacy of immune checkpoint inhibitors (ICIs) in diverse cancers, especially in non-small cell lung cancer (NSCLC) and melanoma [1, 2]. High TMB presents enriched clonal neoantigens and increased tumor immunogenicity, which can improve the response to cancer immunotherapy [3]. However, as host immunity is also significant to eliminate cancer cells, its clinical impact on cancer immunotherapy is still largely unknown. Immunosenescence, which refers to the decline of immune system with aging, may contribute to reduced tumor cell clearance efficiency in body, leading to increased cancer incidence in the elderly [4].

Based on these facts and evidence, we hypothesized that TMB could show better predictive value for cancer immunotherapy in young patients than in elderly patients in NSCLC. In order to test the hypothesis, published clinical data was identified through systematic literature search. Durable clinical benefit (DCB), progression-free survival (PFS) and overall survival (OS) were adopted as endpoints for assessment. Detailed methods were explained in Additional file 1.

We identified three NSCLC immunotherapy cohorts containing 665 patients [1, 5, 6]. Detailed characteristics of patients included were summarized in Additional file 2: Table S1.

Firstly, as was shown in Fig. 1, high TMB was capable of predicting better DCB in agelow group. However, the predictive power was insignificant in agehigh group, indicating high TMB failed to forecast clinical benefit in the group.

Fig. 1
figure 1

ROC curve analysis of the association between TMB and DCB in young and elderly patients in NSCLC. ROC curves of (a) Rizvi cohort, (b) Hellmann cohort. ROC: receiver operator characteristic; TMB: tumor mutation burden; DCB: durable clinical benefit; NSCLC: non-small cell lung cancer; AUC: area under curve; CI: confidence interval

Secondly, it was found that in agelow group, high TMB dramatically illustrated improved PFS (Rizvi cohort: Hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.35, 0.80, P = 0.003, Fig. 2a; Hellman cohort: HR 0.26, 95% CI 0.08, 0.45, P < 0.001, Fig. 2c). The results were still significant in multivariate analysis (Rizvi cohort: Adjusted HR 0.54, 95% CI 0.36, 0.82, P = 0.004; Hellman cohort: Adjusted HR 0.23, 95% CI 0.09, 0.55, P = 0.001). However, there was no correlation between PFS and TMB level in agehigh group (Rizvi cohort: HR 1.03, 95% CI 0.70, 1.51, P = 0.898, Fig. 2b; Hellman cohort: HR 0.71, 95% CI 0.32, 1.55, P = 0.388, Fig. 2d). In the adjusted model, the conclusion was unchanged (Rizvi cohort: Adjusted HR 1.10, 95% CI 0.71, 1,71, P = 0.677; Hellman cohort: Adjusted HR 0.60, 95% CI 0.24, 1.50, P = 0.275). Then, the result of meta-analysis further illustrated that predictive power of TMB was more significant in agelow group than in agehigh group (Heterogeneity between two groups: P = 0.007, Fig. 3). In addition, in order to exclude whether the specific cutoff of TMB had an effect on the result, TMB at the highest quarter was adopted as another cutpoint. As was shown in Additional file 2: Figure S1, high TMB still showed better predictive power of PFS in agelow group rather than in agehigh group (Heterogeneity between two groups: P = 0.012).

Fig. 2
figure 2

Kaplan–Meier curves and HR analysis of the association between TMB and PFS in young and elderly patients in NSCLC. Kaplan–Meier curves of (a) Agelow group and (b) Agehigh group in Rizvi cohort, (c) Agelow group and (d) Agehigh group in Hellmann cohort. HR: hazard ratio; TMB: tumor mutation burden; PFS: progression-free survival; NSCLC: non-small cell lung cancer; CI: confidence interval

Fig. 3
figure 3

Forest plot of the association between TMB and PFS in young and elderly patients in NSCLC. TMB: tumor mutation burden; PFS: progression-free survival; NSCLC: non-small cell lung cancer; HR: hazard ratio; CI: confidence interval

Moreover, the predictive value of TMB for OS of immunotherapy was evaluated in the two age groups. When using median TMB as cutoff, though both agelow (HR 0.72, 95% CI 0.46, 1.07, P = 0.112, Additional file 2: Figure S2A) and agehigh (HR 1.03, 95% CI 0.72, 1.47, P = 0.881, Additional file 2: Figure S2B) groups showed insignificant predictive value, the former presented a better tendency. When adopting TMB at the highest quarter as cutpoint, high TMB illustrated meaningful predictive power in agelow group (HR 0.43, 95% CI 0.30, 0.76, P = 0.007, Additional file 2: Figure S2C), while it was still insignificant in agehigh group (HR 0.80, 95% CI 0.53, 1.19, P = 0.282, Additional file 2: Figure S2D). In multivariate analysis, the conclusion was unchanged (Agelow group: Adjusted HR 0.43, 95% CI 0.24, 0.75, P = 0.003; Agehigh group: Adjusted HR 0.82, 95% CI 0.54, 1.25, P = 0.354).

In the present study, we found that TMB could present better predictive value on the response to cancer immunotherapy in young patients than in elderly patients in NSCLC. High TMB is associated with enhanced tumor immunogenicity [3], which is an important factor in determining efficacy of cancer immunotherapy [7]. However, in addition to sufficient antigen presentation, a dynamic host immunity may also be necessary for eliminating cancer cells during ICIs therapy. In the process of aging, immune cells are gradually reduced in quantity and becoming defective [4]. Interestingly, PD-1/PD-L1 blockade could not completely restore exhausted T-cell responses in aged mice [8], suggesting the significance of basic immunity of host to confront tumor. To note, age itself may not be an appropriate marker to predict cancer immunotherapy response due to its complex influence on body besides host immunity [9].

There are several strengths in the study. Firstly, different studies including a large number of patients were analyzed, which increased the credibility of the results. Besides, both univariate and multivariate analyses were adopted, which improved the accuracy of the conclusion. However, there are quite a few limitations in the present study. First of all, different TMB testing methodologies and cutoffs were utilized, as there is still no uniform standard, which could lead to heterogeneity of the results. In addition, analysis in the study was conducted only in NSCLC, while related open access data in most cancers are still insufficient.

In conclusion, we revealed that the predictive power of TMB on ICIs therapy was better in young patients than in elderly patients in NSCLC. Therefore, more effective markers need to be identified to differentiate the efficacy of cancer immunotherapy in elderly patients in NSCLC. In addition, the combination of tumor immunogenicity and host immunity evaluation may better identify patient subgroups which are suitable for cancer immunotherapy.