*5.4. TCR diversity and MHC Molecules*

Thanks to the diversity of the TCR, T cells can recognise a multitude of different epitopes through TCR–MHC interaction, which is associated with effective control of viral infections, other pathogens and tumour cells. This diversity is generated by a complex mechanism based on genetic recombination of DNA, leading to different antigenic specificities [294].

Following immunotherapy based on checkpoint inhibitors, there has been increased interest in analysing TCR diversity, as it allows for a better understanding of the patient's immune system. TCR diversity is estimated to be 108–1015 and can be evaluated by NS, spectrometry, qPCR multiplex or immune phenotyping. The impact and clinical outcome of immunotherapy has been shown to be related to the diversity of TCR in peripheral blood [294]. Blocking CTLA-4 with tremelimumab has been shown to diversify the peripheral T cell pool, highlighting the effect of this class of immunomodulatory antibodies [337].

The effective response generated by antigen-specific T cells after recognition of tumour antigens expressed on MHC class I molecules can be affected by germline and somatic MHC class I genotype variations [281]. Patients with advanced melanoma and NSCLC treated with checkpoint inhibitors who were heterozygous at the MHC class I locus had better overall survival than those who were homozygous [338]. This is associated with increased clonality of TCR and clonal expansion of T cells following the use of this immunotherapy. The somatic loss of MHC class I heterozygosity in these patients results in poor outcome, which is associated with impaired recognition of neo-antigens by CD8+ T cells due to structural changes at the class I locus [281].

It is necessary to analyse the diversity of TCR and MHC molecules and their interactions in order to achieve a personalised and beneficial immunotherapeutic treatment for each type of cancer, as it has been shown that the basal diversity of TCR in peripheral blood is associated with clinical outcomes [294,339].
