Abstract
The Gram-positive bacterium Listeria monocytogenes (Lm) is an emerging platform for cancer immunotherapy. To date, over 30 clinical trials have been initiated testing Lm cancer vaccines across a wide variety of cancers, including lung, cervical, colorectal, and pancreatic. Here, we assessed the immunogenicity of an Lm vaccine against the colorectal tumor antigen GUCY2C (Lm-GUCY2C). Surprisingly, Lm-GUCY2C vaccination did not prime naïve GUCY2C-specific CD8+ T-cell responses towards the dominant H-2Kd-restricted epitope, GUCY2C254-262. However, Lm-GUCY2C produced robust CD8+ T-cell responses towards Lm-derived peptides suggesting that GUCY2C254-262 peptide may be subdominant to Lm-derived peptides. Indeed, incorporating immunogenic Lm peptides into an adenovirus-based GUCY2C vaccine previously shown to induce robust GUCY2C254-262 immunity completely suppressed GUCY2C254-262 responses. Comparison of immunogenic Lm-derived peptides to GUCY2C254-262 revealed that Lm-derived peptides form highly stable peptide-MHC complexes with H-2Kd compared to GUCY2C254-262 peptide. Moreover, amino acid substitution at a critical anchoring residue for H-2Kd binding, producing GUCY2CF255Y, significantly improved stability with H-2Kd and rescued GUCY2C254-262 immunogenicity in the context of Lm vaccination. Collectively, these studies suggest that Lm antigens may compete with and suppress the immunogenicity of target vaccine antigens and that use of altered peptide ligands with enhanced peptide-MHC stability may be necessary to elicit robust immune responses. These studies suggest that optimizing target antigen competitiveness with Lm antigens or alternative immunization regimen strategies, such as prime-boost, may be required to maximize the clinical utility of Lm-based vaccines.
Highlights
Due to the unprecedented success of immune checkpoint inhibitors (ICIs) and adoptive cell therapy, immunotherapy has established itself as a pillar of cancer management alongside chemotherapy, surgery, targeted therapies, and radiotherapy [1, 2]
For in vitro validation studies, the mouse macrophage cell line J774A.1 cultured in DMEM supplemented with 10% FBS was infected at a 10:1 multiplicity of infection with control or GUCY2C Listeria monocytogenes (Lm)
Lm-GUCY2C was produced using a construct composed of the actA promoter, an enhancer, and a fusion protein of a modified version of the first 100 amino acids of actA (ActAN100*) and residues 23-429 of murine GUCY2C (Figure 1A and Supplementary Figure 1)
Summary
Due to the unprecedented success of immune checkpoint inhibitors (ICIs) and adoptive cell therapy, immunotherapy has established itself as a pillar of cancer management alongside chemotherapy, surgery, targeted therapies, and radiotherapy [1, 2]. While ICIs have been practice-changing, only 20% of patients respond to ICI therapy [3, 4]. Responsiveness to ICI therapy is associated with immunologically “hot” tumors characterized by significant immune cell infiltration [5, 6]. In this context, there has been renewed interest in utilizing cancer vaccines as agents that expand tumor-specific T cells and promote T-cell infiltration into tumor microenvironments, working synergistically with ICI therapy [3, 4, 7]. A greater understanding of vaccine vector biology is urgently needed
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