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

Abstract

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.

Figure 1.. Nucleotide insertion or deletion produces altered proteins associated with immunogenicity.

A. Insertion or deletion (INDEL) of nucleotides in the open reading frame (ORF) of mRNA can cause stop codon shifts and results in the production of altered proteins that are considered foreign by the host immune system. B. Following transcription and translation of INDEL proteins, proteasomal degradation cleaves aberrant proteins into shorter peptides. The transporter associated with antigen processing (TAP) transports these peptides to the endoplasmic reticulum (ER) where they are associated with major histocompatibility complex I (MHC-I) molecules. Antigen–MHC-I complexes are then transported to the cell surface where they are presented to T cells via the T cell receptor (TCR) and have potential to induce T cell activation.

Figure 2.. TE activation can promote immune rejection by triggering viral mimicry or generating a TE-associated antigen.

Expression of transposable elements (TEs) is usually tightly regulated or repressed. Suppression is often mediated by DNA hypermethylation and repressive histone marks, such as dimethylated or trimethylated histone H3 Lys9 (H3K9me2 and H3K9me3, respectively) and trimethylated histone H3 Lys27 (H3K27me3) and located in heterochromatic regions. However, altered epigenetic states associated with cancer or epigenetic drugs, such as DNA hypomethylating agents or histone methyltransferase inhibitors, can allow TEs activation. Derepression of TE elements might lead to their transcription or promote genomic instability. TE transcription can produce atypical nucleic acid species, such as double-stranded RNAs (dsRNAs) and single-stranded RNAs (ssRNAs), that form complex double stranded structures, which can mimic an exogenous viral infection and trigger the activation of endogenous nucleic acid pattern recognition receptors (MDA5 and RIG-I, respectively). TE transcription might also produce dsDNAs or DNA–RNA hybrids that could activate the CGAS–STING pathway. Activation of MDA5, RIG-I, or CGAS culminates with the activation of TBK1, which in turn phosphorylates and activates several transcription factors, such as IRF3 and IRF7, to induce expression of interferon (IFN) response genes. Activation of these genes promotes secretion of inflammatory IFNs and chemokines to promote recruitment of immune cells. TE activation can also produce translatable TE transcripts or TE-coding gene chimeric transcripts that generate TE-associated antigens. If the TE gene encodes a surface protein (for example, ERV-E4 env), then it can generate a neoepitope directly. Other TE-associated protein products might be sampled by the endogenous immunoproteasome and presented to T cells in a class I MHC-dependent manner. Alternatively, TE-associated proteins could be sampled by dendritic cells in the TME or in draining lymph nodes and presented on class II MHC molecules.