Treatment options for cancer have focused around the “3 pillars” of therapy: surgery, chemotherapy, and radiotherapy. A recent shift towards a 4th pillar, immunotherapy, aims to elicit an anti-cancer immune response. Cancer immunotherapy is one of the most significant breakthroughs in recent years, however, patients do not always exhibit curative responses, prompting the need to combine with other approaches. Thus, there is renewed focus surrounding the idea that radiotherapy can also stimulate T cells to recognise tumour cells, inducing an immune-mediated anti- tumour effect termed the abscopal effect.
For immunosurveillance, the human leukocyte antigen (HLA) molecules on cells present peptide antigens to T cells. The series of peptides that are displayed in the antigen binding grooves are defined as the immunopeptidome. The identification and study of these peptides is a powerful tool for identifying novel cancer antigens. Our aim is to identify a profile of the immunopeptidome pre- and post-radiotherapy in colorectal tumours.
Irradiation of a malignant colorectal cell line, SW480, halted active cellular proliferation but was sub-lethal and resulted in increased HLA class I expression. Subsequently, we investigated whether the immunopeptidome of these cells was also altered by the irradiation. Briefly, the immunopeptidomes of irradiated and non-irradiated SW480 cells were investigated by isolating peptides from purified HLA class I molecules and their identification evaluated by tandem mass spectrometry (MS/MS). This analysis revealed that irradiation alters the antigenic landscape of cancer cells. Irradiated cells demonstrated a significant increase in the total number of peptides presented, with a unique radiation-induced peptide repertoire emerging, curiously with a shift in length from 9mers towards 12mer peptides. Furthermore, there were more unique source proteins in the irradiated condition; DNA damage response dominated the pathways contributing to these new source proteins. This provides a proof-of-concept that irradiation impacts the immunopeptidome and consequently alters what is scrutinised by T cells.
Additional work included the preliminary analysis of colorectal biopsies. Building a picture of the immunopeptidome in healthy, tumorous, and irradiated tissue will provide novel insights into the immunobiology of radiotherapy which can be translated into innovative treatment options such as T cell- based immunotherapy.