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  • br Fig Kaplan Meier plots showing A overall survival and


    Fig. 2. Kaplan-Meier plots showing (A) overall survival and (B) progression-free survival of patients with and without TP53 mutations from ICI initiation. NR: Not Reached.
    instability [30], thereby spurring tumor immunogenicity by generating tumor neo-antigens or resulting in mutations in dominant oncogenes, such as KRAS [31]. That gain in tumor immunogenicity fueled by the loss of TP53 may also cause increased recruitment of cytotoxic T lym-phocytes into the tumor stroma, consequently potentiating the efficacy of ICI [32]. Additionally, it has been proven that destabilizing TP53 mutations could lead to altered unfolded TP53 proteins, which may also independently constitute tumor-specific Fer-1 enhancing T cell re-activity, when involving major histocompatibility (MHC) Class I mo-lecules [33].
    Conversely, wild-type TP53 is thought to also be involved in PD-L1 expression regulation. As shown by Cha et al. in 323 surgically-resected lung adenocarcinoma cases, TP53 mutated status, as assessed in this study by positive immunochemistry staining with anti-TP53 antibody, which is only partly correlated with TP53 mutations, was actually as-sociated with higher PD-L1 expression in tumor cells [14]. However, evaluating TP53 mutational status with immunohistochemical assay appears questionable, since mechanisms other than mutations could lead to intracellular accumulation of TP53 protein, which also depends on the type of TP53 mutation [34]. It has been also demonstrated by Cortez et al., in vitro and in a syngeneic mouse model presenting with lung adenocarcinoma harboring R172H TP53 mutation, that TP53 regulates PD-L1 expression by modulating the transcription of a specific microRNA, the miR-34, which directly binds with and inhibits the PD-L1 gene [35].
    Therefore, one could speculate that TP53 loss leads to PD-L1 ex-pression derepression in tumor cells, likely optimizing the efficacy of anti-PD1 and anti-PD-L1 inhibitors. However, PD-L1 did not correlate with survival, while multivariate analysis showed TP53 mutations were independently associated with better OS, suggesting that expression of  Lung Cancer 132 (2019) 65–71
    PD-L1 did not represent a confounding factor in our series. In recent years, wild-type TP53 has also been hailed as a guardian of immune integrity. One of TP53′s most essential roles has been shown to be obviating autoimmunity, notably by modulating the induction of T regulatory cells through TP53- mediated Foxp3 transcription [36,37]. Thus, TP53 loss may also reduce tumor immuno-tolerance and foster induction of immune cytotoxic effectors in inhibiting T cell polarization towards T regulatory cell phenotype.
    Our study encountered several limitations: first, its retrospective nature, with the lack of blinded independent assessment of objective response, although ORR was a secondary endpoint. Second, the limited size of our single-center series could have resulted in bias and lack of statistical power. Notably, keeping in mind that targeted somatic NGS is only routinely performed in our center for lung non-squamous carci-noma, an essential bias consists in the fact that 73.6% of patients in our cohort presented with adenocarcinoma. However, it has been demon-strated that the type of hotspot mutations of TP53 gene were similar between lung adenocarcinoma and squamous lung cancer, especially in current or former smokers, although the incidence of these mutations was notably lower, for some authors, in adenocarcinoma than in squamous cancer subtype (46% versus 81%, respectively) [27]. Ad-ditionally, our study was not specifically designed to demonstrate any predictive value of TP53 mutations, giving the lack of a control group of patients not treated by immunotherapy.
    Finally, the significant association between TP53 mutations and response or survival under ICI may be merely mediated through TMB, which has been found to positively correlate with favorable outcomes under ICI [8,9,23]. In our study, we did not quantify tumor mutation load using an appropriate assay, either WES or the surrogate commer-cially available Foundation One™ assay, which is not routinely avail-able in Europe taking into account for its high non-reimbursed cost. Moreover, the aforementioned biological effects of a disabled TP53 gene, including PD-L1 expression de-repression, decreased induction of T-reg lymphocytes or the auto-antigenicity of a mutated p53 protein, should not be overlooked for the benefit of genomic instability spurred by a mutated TP53 gene. Thus, we believe that TP53 mutational status could indirectly provide a measure of genetic instability in a quicker, easier, and cheaper way than wide somatic NGS, and should be pro-spectively tested to check if it could then routinely help clinicians in treatment decision-making.