Human tumours are colonized by microorganisms1, collectively referred to as the tumour microbiota, that may have an effect on the microenvironment of the tumour — for instance, by inflicting irritation or native immune suppression2. This can result in modifications in how the physique’s immune system responds to the tumour, and may alter responses to remedy3. But are intratumoral micro organism themselves acknowledged by the immune system? Writing in Nature, Kalaora et al.4 present that bacterial protein fragments referred to as peptides are presented to the immune system on the floor of tumour cells, and are acknowledged by immune cells referred to as T cells. This discovery would possibly be exploited for most cancers immunotherapeutics.
Molecules referred to as tumour antigens allow the immune system to distinguish tumour cells from wholesome cells. Every cell comprises antigen-processing equipment, which permits antigen-derived peptides to be presented to the immune system by specialised molecules referred to as human leukocyte antigens (HLAs) on the cell floor. HLA-presented peptides which can be acknowledged by immune cells are referred to as epitopes.
Tumour antigens are available two principal classes: tumour-associated and tumour-specific5. Tumour-associated antigens are expressed in regular tissues in addition to in tumours, and so don’t readily activate immune responses. But if immune responses are mounted, there’s a danger of dangerous autoimmune reactions towards the conventional tissues that categorical the antigen. Nonetheless, as a result of tumour-associated antigens are sometimes present in a number of kinds of tumour and in many individuals who’ve most cancers, they will be good targets for broadly relevant immunotherapies. By distinction, tumour-specific antigens are expressed solely on tumour cells and so are ideally suited targets for mounting a selected immune assault towards tumours. One subtype, neoantigens, arises from tumour-specific gene mutations, and so neoantigens are sometimes tumour- and patient-specific. Targeting neoantigen-derived peptides (referred to as neoepitopes) subsequently necessitates really customized immunotherapies.
A pores and skin most cancers referred to as melanoma has three recognized courses of tumour-associated antigen, and its cells sometimes carry many genetic mutations, leading to a excessive chance of neoantigens6. It has subsequently been on the forefront of tumour-antigen discovery and cancer-immunotherapy growth7–9. It is thus becoming that Kalaora et al. use melanoma samples to explain one other potential class of tumour antigen.
The authors got down to examine the bacterial composition of 17 melanoma metastases (tumours fashioned when a most cancers spreads from its authentic website to different areas of the physique) from 9 folks. They discovered that the composition of micro organism was extremely comparable in several metastases from the identical particular person, and generally in samples from completely different folks. This discovering signifies that specific bacterial species are frequent to melanoma, consistent with a earlier research reporting tumour microbiota particular to various kinds of most cancers1. The authors additionally confirmed that these micro organism have been current in melanoma cells, reasonably than within the surrounding extracellular microenvironment.
Kalaora and colleagues went on to research whether or not peptides from these intracellular micro organism are presented to the immune system in the identical means as are different intracellular antigens. To this finish, they used an method primarily based on mass spectrometry referred to as immunopeptidomics, which permits direct detection of HLA-presented peptides. They discovered near 300 peptides of their samples, from 33 bacterial species. Several peptides have been present in a couple of tumour from the identical individual and in tumours from completely different folks.
The authors subsequent requested whether or not the bacterial peptides are really presented by melanoma cells, reasonably than by immune cells referred to as antigen-presenting cells (APCs) that detect, take up and current pathogens to different cells of the immune system. The authors used an immune-cell marker protein to separate cells from two melanoma samples into APCs and tumour cells. Immunopeptidomics revealed that each teams of cell presented bacterial peptides. A subset of the peptides was presented by each APCs and tumour cells, indicating that the identical peptide can each provoke an immune response by means of presentation on APCs and be a goal for immune assault on tumour cells. The researchers then confirmed that T cells (which acknowledge HLA-presented peptides) remoted from the melanomas reacted to the recognized bacterial peptides, together with a number of the peptides shared between tumours and people.
Taken collectively, Kalaora and colleagues’ outcomes level to the likelihood that tumour-displayed bacterial peptides are a beforehand unidentified class of tumour antigen (Fig. 1). However, a number of questions stay. To be bona fide tumour antigens, the recognized bacterial species mustn’t invade non-tumour tissue and their peptides mustn’t be presented on HLAs on non-tumour cells. If this presentation have been detected, the peptides wouldn’t qualify as immunotherapy targets. In addition, the bacterial peptides appear to be fairly plentiful (not less than, in contrast with the numbers of recognized melanoma neoepitopes7), so why does the physique not mount an efficient immune response towards melanomas? Further research of tumour-displayed bacterial peptides together with affected person data will be wanted to elucidate the potential medical function of the peptides. Such information would possibly assist researchers to pick out appropriate bacterial targets for cancer-immunotherapy approaches.
In conclusion, the bacterial peptides recognized by Kalaora et al. could be enticing targets for immunotherapy. As bacterial peptides are ‘non-self’, it ought to be comparatively straightforward to elicit sturdy immune responses towards them, and there would be no considerations about autoimmunity if it could be ascertained that they aren’t presented on any regular tissue. Thus, tumour-displayed bacterial peptides could function tumour-specific antigens shared between folks — a uncommon and helpful mixture for therapeutics, up to now seen solely in virally induced tumours, through which epitopes can be derived from viral cancer-causing proteins5. Recent information point out that tumour-invading micro organism would possibly be a standard phenomenon1,2. Kalaora and colleagues’ work could subsequently lay the inspiration for figuring out shared tumour-specific antigens in a variety of tumour varieties.