Biology subjects

Lechner, M. G.

Publications and source records attributed to Lechner, M. G..

3 recordsLinked to original sources

bioRxiv2022

Clonally-Expanded, Thyrotoxic Autoimmune Mediator CD8+ T cells Driven by IL21 Contribute to Checkpoint Inhibitor Thyroiditis

Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) cancer therapy and is an increasing clinical challenge with the expanding use of these treatments. To date, human immunopathogenic studies of immune related adverse events (IRAEs) have relied upon sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from subjects with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates to those from subjects with spontaneous autoimmune Hashimotos thyroiditis (HT) or no thyroid disease. Single cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6+ CD8+ T cells ("CD8+ autoimmune mediators) present in ICI-thyroiditis, but not HT or healthy controls. Furthermore, we identified a crucial role for interleukin 21, a cytokine secreted by intrathyroidal T follicular (Tfh) and T peripheral helper (Tph) cells, as a driver of these thyrotoxic CD8+ autoimmune mediators. In the presence of IL21, human CD8+ T cells acquired the autoimmune mediator phenotype with upregulation of cytotoxic molecules (IFN{gamma}, granzyme); the chemokine receptor CXCR6; and thyrotoxic capacity. We validated these findings in vivo using a novel mouse model of IRAEs, and further demonstrated that genetic blockade of IL21 signaling protected ICI-treated mice from thyroid immune infiltration. Taken together these studies reveal novel mechanisms and therapeutic targets by which IL21+ Tfh/Tph cells drive thyrotoxic CD8+ autoimmune mediators for the development of IRAEs in humans. One Sentence SummaryScRNAseq reveals a novel role for CD8+ autoimmune mediators and IL21+ T helper cells in the pathogenesis of human checkpoint inhibitor thyroiditis.

immunology↗

bioRxiv2022

Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors.

The mechanism by which ICI (immune checkpoint inhibitor) induce durable antitumor T cell activity remains inadequately defined. Tumors from melanoma patients who responded to ICI or MAPK pathway inhibitors (MAPKi) therapy generally displayed increased T cell infiltration and interferon gamma (IFN{gamma}) pathway activation. Yet, the rate of durable tumor control after ICI is almost twice that of MAPKi. Comparing the transcriptome of cohorts of melanoma patients treated with ICI or MAPKi therapy, we discovered that response to ICI is associated with CXCL13-driven recruitment of CXCR5+ B cells with higher clonal diversity than MAPKi. Higher B cell receptor (BCR) diversity allows presentation of diverse tumor antigens by B cells, resulting in robust increases of IFN{gamma} pathway activity and CXCL13 expression in tumor reactive CD8 T cells after ICI therapy. Accordingly, ICI-treated melanoma patients, but not MAPKi, whose tumors displayed higher BCR diversity and IFN{gamma} pathway score, survived significantly longer than those with either one or none. Thus, response to ICI, but not to MAPKi therapy, induces the recruitment of clonally diverse antigen presenting B cells that activate tumor specific, cytotoxic CD8 T cells to effect a durable antitumor immune response. Our result suggests that enhancing B cells tumor antigen presentation to intratumoral CD8 T cells can increase the rate of long-term response to ICI therapy.

cancer biology↗

bioRxiv2022

Inhibition of the IL-17A axis Protects against Immune-related Adverse Events while Supporting Checkpoint Inhibitor Anti-tumor Efficacy

Checkpoint inhibitor (ICI) immunotherapy leverages the bodys own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune related adverse events (IrAE) may lead to treatment interruption, permanent organ dysfunction, hospitalization and premature death. Thyroiditis is one of the most common IrAE, but the cause of thyroid IrAE remains unknown. Here we present a novel mouse model in which checkpoint inhibitor therapy leads to multi-organ autoimmune infiltrates and show that activation and infiltration of Type 3 immune cells including IL17A+ ROR{gamma}t+ CD4+ (T helper 17 or Th17) and gamma delta 17 ({gamma}{delta}T17) T cells promote thyroid IrAE development. IL-17A+ T cells were similarly found in thyroid specimens from cancer patients treated with ICI who developed thyroid IrAE. Furthermore, antibody-based inhibition of IL-17A, a clinically available therapy, significantly reduced thyroid IrAE development in ICI-treated mice. Finally, combination of IL-17A neutralization with ICI treatment in multiple tumor models did not reduce ICI anti-tumor efficacy. These studies suggest that targeting Th17 and {gamma}{delta}17 function may reduce IrAE without impairing ICI anti-tumor efficacy and may be a generalizable strategy to address IL17-mediated IrAE.

immunology↗