5.2.6. Tumoral Genomics Biomarkers

Effective immune responses to T-cell checkpoint inhibitors in some cancers correlate with the mutational load on the tumour cell [152,314]. Many of these mutations are likely to be transient and will be influencing the process of immunoedition by exerting selective pressure on the immune system. Mutational load or the emergence of neoantigens could be predictive biomarkers for the tumour response to immunotherapy agents if this hypothesis is ultimately established [282].

In one study, the entire exome was sequenced to analyse the effect of cancer genomes on the response to ipilimumab in melanoma patients. A high mutational load and the number of non-anonymous mutations per exome were found to correlate with improved overall survival. In addition, they identified 101 motifs of tetrapeptides in nonameric peptides located in the peptide-binding cleft of MHC class I molecules. These tetrapeptides were shared exclusively by patients who had long-term clinical benefit [315]. In another study, the exome of non-small cell lung cancer treated with pembrolizumab was sequenced and a high burden of non-synonymous mutations in the tumours was seen. Clinical response correlates with the molecular signatures of tobacco-related carcinogenic mutations, increased neoantigen load, and mutations in the DNA repair pathway. Pembrolizumab improved the reactivity of neo-antigen-specific CD8+ T cells and is associated with tumour regression [152].

With expression microarray technologies, genes that play an important role in immune cell biology and are highly expressed in the tumour expression profiles of some patients have been identified. These genes reflect the relative abundance of different populations of tumour-infiltrating leukocytes. From this, robust and reproducible associations between immune gene signatures in solid tumours and clinical outcomes have been identified, providing prognostic information [294]. For example, high gene expression reflecting T, B, and NK cell involvement in metastatic melanoma is associated with prolonged overall survival and survival without metastasis [316].

Immune genes have predictive potential in the context of immunotherapy. These genes include T cell surface markers (CD3, CD277, CD27, CD38), cytotoxic factors (GZMB), and tissue-rejection-related cytokines (CXCL9, CXCL10, CCL4, CCL5) [294,317].
