Tumor Mutation Burden in lung cancer

Abstract

Abstract The clinical success of PD-1 pathway-targeted immunotherapy in a subset of lung cancer patients is imperfectly predicted by PD-L1 expression alone. Very unlike the targeting of activating driver mutations, PD-L1 represents a continuous variable that is semi-quantitatively assessed currently by immunotherapy and only relatively enriches for those more or less likely to benefit. The major mechanism of action is thought to be overcoming cytotoxic T-cell senescence and anergy, and these cells target peptide neo-antigens in the context of class I MHC. Thus the likelihood of an effective immune response is thought to be related to the presence, clonality, and number of somatic neo-epitopes. In many settings, simply counting the number of clonal somatic non-synonymous mutations is associated with increased clinical benefit, but there are many uncertain variables associated with this enumeration. The method and scope of the mutation analysis, source of DNA, the specific genes chosen, the thresholds for positivity, and the inclusion of frame-shift mutational neo-epitopes are all variables of uncertain impact in the different methods. In addition, T-cells do not recognize DNA mutations, but rather fragments of expressed proteins that have been processed and presented on MHCI, a process that involves dozens of steps, alterations in each of which can affect the probability of a given mutation being an effective T-cell target. The state of the art of tumor mutation burden assessment will be reviewed and its potential role as a biomarker for immunotherapy will be discussed.