Immunogenicity in renal cell carcinoma: shifting focus to alternative sources of tumour-specific antigens

Renal cell carcinoma (RCC) comprises a group of malignancies arising from the kidney with unique tumour-specific antigen (TSA) signatures that can trigger cytotoxic immunity. Two classes of TSAs are now considered potential drivers of immunogenicity in RCC: small-scale insertions and deletions (INDELs) that result in coding frameshift mutations, and activation of human endogenous retroviruses. The presence of neoantigen-specific T cells is a hallmark of solid tumours with a high mutagenic burden, which typically have abundant TSAs owing to non-synonymous single nucleotide variations within the genome. However, RCC exhibits high cytotoxic T cell reactivity despite only having an intermediate non-synonymous single nucleotide variation mutational burden. Instead, RCC tumours have a high pan-cancer proportion of INDEL frameshift mutations, and coding frameshift INDELs are associated with high immunogenicity. Moreover, cytotoxic T cells in RCC subtypes seem to recognize tumour-specific endogenous retrovirus epitopes, whose presence is associated with clinical responses to immune checkpoint blockade therapy. Here, we review the distinct molecular landscapes in RCC that promote immunogenic responses, discuss clinical opportunities for discovery of biomarkers that can inform therapeutic immune checkpoint blockade strategies, and identify gaps in knowledge for future investigations.