The vaccine-site microenvironment: impacts of antigen, adjuvant, and same-site vaccination on antigen presentation and immune signaling

Abstract

BackgroundA goal of cancer vaccines is to induce strong T cell responses to tumor antigens, but the delivery method, schedule, and formulation of cancer vaccines have not yet been optimized. Adjuvants serve to increase the immune response against vaccine antigens. However, little is known about the impact of adjuvants plus antigen and their delivery schedule on the immunologic milieu in the vaccine-site microenvironment (VSME). We hypothesized that antigen processing and presentation may occur directly in the VSME, that adding the toll-like receptor 3 (TLR3) agonist polyICLC (pICLC) would enhance markers of immune activation, and that the immune signatures would be enhanced further by repeated vaccination in the same skin site rather than after multiple vaccines in different skin locations.MethodsUsing RNA sequencing, we evaluated VSME biopsies from patients undergoing subcutaneous/intradermal peptide vaccination against melanoma, with incomplete Freund’s adjuvant (IFA) with or without pICLC. Differential gene expression analyses and gene set enrichment analyses were performed using R. False discovery rate corrected p values <0.05 were considered significant.ResultsWe found that addition of peptide antigens to IFA enhanced antigen presentation pathways and a tertiary lymphoid structure gene-signature locally at the VSME. Addition of pICLC to IFA + peptide induced an immunologically favorable VSME 1 week after injection but had little impact on the VSME after three injections, compared with IFA + peptide alone. Repeated same-site injection of IFA + peptide antigens induced a VSME with more dendritic cell activation, Th1 dominance, and TLR adaptor protein gene expression than that induced by injections at different, rotating skin locations.ConclusionsThese data suggest that the vaccine-site itself may be a critically important location contributing to vaccine immunity rather than just the draining lymph node, that IFA induces a favorable VSME with TLR agonist being most beneficial early in the vaccine course, and that same-site injections lead to persistent stimulation of immune pathways that may be beneficial in eliciting antigen specific T cell expansion.

"Original Antigenic Sin" in SARS-CoV-2 Vaccination Followed by Infection

“…Therefore, TLS reacting to successive cognate antigenic challenges in the OAS scenario is a plausible explanation. The stimulus caused by the infection may unleash the production of antibodies against the SARS-CoV-2 vaccine antigens, and they respond in the tertiary lymphoid follicles [ 10 ].…”

Tertiary lymphoid structures in cancer: immune mechanisms and clinical implications

“…Combination therapy, such as protein vaccine combined with adjuvant, 196 DC vaccine combined with dasatinib, increases the formation of TLS and enhances the immune response in melanoma 197 . As a component of adjuvant, TLR3 agonist injection at the tumor vaccination site can promote the expansion of antigen‐specific T cells and enhance the immune response in TLS 198 …”

Peptide emulsions in incomplete Freund’s adjuvant create effective nurseries promoting egress of systemic CD4+and CD8+T cells for immunotherapy of cancer

“…Interestingly, however, recent data suggest that the vaccine site itself may be a critically important location contributing to vaccine immunity rather than just the draining lymph node, that IFA induces a favorable VSME, with TLR agonist being most beneficial early in the vaccine course, and that same-site injections lead to persistent stimulation of immune pathways that may be beneficial in eliciting antigen-specific T cell expansion ( figure 1 ). 47 …”