Aubergeon, L. | bioRxiv Science

bioRxiv2024

Targeting B and T lymphocyte attenuator regulates lupus disease development in NZB/W mice

B and T Lymphocyte Attenuator (BTLA) is a co-inhibitory receptor expressed by most immune cells, playing a role in negatively regulating immune responses. Studies in MRL/lpr lupus mice deficient for BTLA, indicate that BTLA has a protective role in lupus. We have previously shown an altered BTLA expression by regulatory T cells and an impaired capacity of BTLA to inhibit CD4+ T cell activation in lupus patients. In this study, we thoroughly analyzed BTLA expression and function in the NZB/W lupus-mouse model. We found that diseased NZB/W mice exhibit a BTLA expression and function pattern similar to that observed in lupus patients, emphasizing the importance of this mouse model in evaluating the therapeutic potential of targeting BTLA. Administration of a monoclonal anti-BTLA antibody (clone 6F7, which displays agonist properties ex vivo) into pre-diseased NZB/W mice resulted in a delayed onset of proteinuria, limited kidney damages and an increased survival rate compared to isotype-treated mice. This beneficial effect was associated with a decrease in circulating B cell frequency and required continuous exposure to the antibody. Regarding its mode of action, we demonstrated that the 6F7 antibody is not a depleting antibody and does not block HVEM binding to BTLA, but instead induces BTLA down modulation, leading to a selective reduction of follicular B cell numbers, and exhibits in vivo agonist activity. Overall, our data confirm the involvement of BTLA in lupus pathogenesis and provide the first evidence that BTLA is a potential therapeutic target for the treatment of lupus.

immunology↗

bioRxiv2024

A Mimicry-Based Strategy Between Human and Commensal Antigens for the Development of a New Family of Immune Therapies for Cancer

Peptide vaccines have emerged as a promising strategy for cancer immunotherapy, yet often lack of strong, specific and sustained immune responses against tumor antigens. To achieve a robust immune response, the effective selection of tumour antigens is crucial. While neoantigens trigger potent immune responses, their use suffers from patient specificity and their rarity in low-mutational tumors. Alternatively, the immunogenic potential of tumor-associated antigens (TAAs) is limited by central immune tolerance. Molecular mimicry and T cell cross-reactivity is a proposed mechanism to trigger a robust T cell-mediated antitumor response. Although molecular mimicry between pathogens and tumor antigens has been described, the potential benefits of exploiting this molecular mimicry with commensal bacterial antigens in antitumor immunity have not been thoroughly investigated despite strong evidence that the composition of the human microbiota significantly influences immune competency. Our new approach called OncoMimics, which uses molecular mimicry between commensal bacterial and tumoral antigens to induce cross-reactive cytotoxic T cells against tumor cells. In preclinical studies, vaccination with OncoMimic peptides (OMPs) led to the expansion of CD8+ T cells reacting against homologous tumor-associated antigen peptides and elicits cytotoxic activity against tumor cells. OMPs are efficiently recognized by a prevalent T cell population within the peripheral blood mononuclear cells of healthy individuals. An ongoing clinical trial (NCT04116658) using OncoMimics in patients with glioblastoma demonstrates early, durable, and cross-reactive tumor antigen CD8+ T cell responses with pronounced memory persistence. By overcoming the current vaccine limitations, OncoMimics constitutes a promising strategy for enhancing cancer immunity and improving patient outcomes. Statement of SignificanceThis study introduces OncoMimics, a peptide-based immunotherapy leveraging molecular mimicry to induce robust, cross-reactive T cell responses against tumor antigens, showing promising early results in an ongoing glioblastoma clinical trial (NCT04116658)

immunology↗