Molecular mimicry and cancer vaccine development

Abstract

Background: The development of cancer immunotherapeutic strategies relies on the identification and validation of optimal target tumor antigens, which should be tumor-specific as well as able to elicit a swift and potent anti-tumor immune response. The vast majority of such strategies are based on tumor associated antigens (TAAs) which are shared wild type cellular self-epitopes highly expressed on tumor cells. Indeed, TAAs can be used to develop off-the-shelf cancer vaccines appropriate to all patients affected by the same malignancy. However, given that they may be also presented by HLAs on the surface of non-malignant cells, they may be possibly affected by immunological tolerance or elicit autoimmune responses.

Main body: In order to overcome such limitations, analogue peptides with improved antigenicity and immunogenicity able to elicit a cross-reactive T cell response are needed. To this aim, non-self-antigens derived from microorganisms (MoAs) may be of great benefit.

Keywords: Cancer Vaccines; Microbiota; Molecular Mimicry; T cell cross-reactivity; Tumor-Associated Antigens.

Fig. 1

Molecular mimicry: homology in the TCR facing residues and molecular interaction. The MAGE-A1_{278 − 286} peptide and the homologous peptide derived from Faecalibacterium prausnitzii (WP_158387495.1) are shown bound to the HLA-A*02:01 molecule. The identical residues K₁, E₄, Y₅, I₇ are presented to the TCR αβ chains with the same conformation (A – D). The contact areas in red between the two peptides and the TCR αβ chains are identical (E - H). The areas of contact between the HLA molecule and the TCR αβ chains are identical (yellow and dark blue areas) (I, J)

Fig. 2

Molecular mimicry of gp100 and HCMV peptides. The gp100 MLGTHTMEV peptide and the homologous MLGTHAMLV peptide derived from HCMV are shown bound to the HLA-A*02:01 molecule. The TCR facing residues are presented to the TCR αβ chains with the same conformation (A, B). The contact areas in red between the two peptides and the TCR αβ chains are identical (C, D). The areas of contact between the HLA molecule and the TCR αβ chains are identical (yellow and dark blue areas). PBMCs from HLA-A*02:01 positive healthy subjects were immunized ex vivo with HCMV peptide. After 14 days, IFNγ EliSpot assay was performed restimulating the cells with the same viral peptide or with the paired gp100 peptide. SFU = IFNγ spot forming units (G)

Fig. 3

T cell cross reactivity against homologous peptides. T cells from HCC patient show cross-reactivity with the HCC-specific MLAGHEFQV peptide and the homologous MLAGNAFTA peptide derived from Human Calicivirus. Results were obtained with MHC-class I tetramers for HLA-A*02:01 loaded with the indicated peptides. (modified from Cavalluzzo et al., 2021)

Fig. 4

Molecular mimicry of MAGE-A1 and microbiota peptides. The MAGE-A1_{278 − 286} KVLEYVIKV peptide and the homologous peptides derived from the indicated microbiota bacteria are shown bound to the HLA-A*02:01 molecule. (A) The TCR facing residues are presented to the TCR αβ chains with the same conformation. (B) The contact areas in red between the peptides and the TCR αβ chains are mostly identical. (C) The areas of contact between the HLA molecule and the TCR αβ chains are identical (yellow and dark blue areas). (D) CD8⁺ T cells from a HCC patient (HCC) and a healthy donor (HD) were incubated with the MAGE-A1_{278 − 286} KVLEYVIKV peptide and the indicated homologous peptides derived from microbiota bacteria. Values represent the level of CD8⁺ T cell activation expressed as absolute value of fold-increase

Fig. 5

Microorganism-derived antigens (MoAs) as anti-cancer strategy. (A) The exposure to a large number of microorganisms or the combination with preventive vaccines based on MoAs eventually lead to a broad memory T cell repertoire. This is promptly activated by a tumor presenting shared antigens leading to cancer regression. (B) The exposure to a limited number of microorganisms elicits a narrow memory T cell repertoire and a cancer may develop and progress. A therapeutic vaccine based on MoAs may elicit an effector anti-cancer T cell response against shared tumor antigens leading to cancer regression