Although classical DC (cDC), which are derived from myeloid progenitors,are specialized in antigen processing and (cross)presentation. However, theyalone are sometimes not enough to prime efficient... Show moreAlthough classical DC (cDC), which are derived from myeloid progenitors,are specialized in antigen processing and (cross)presentation. However, theyalone are sometimes not enough to prime efficient CD8+ T-cell responses. Theconcept of DC licensing by CD4+ T-cell “help” for anti-tumor CTL responses wasdiscovered in 1990s. Since then, ample mouse studies have been conducted aimingto discover the mechanism of the “help” signals. In this thesis, I delved intothe molecular mechanisms of CD4+ T-cell “help” as a critical signal that cansuccessfully activate human cDC1 and describe the clinical significance of cDC1licensing in human cancers. I also explored the role of type I interferon(IFN-I) signaling as part of cDC1 licensing machinery, and identified tumor-infiltratingKi67+CXCL13+CD4+ T-cells as IFN-I producers in the context of help delivery tocDC1 in the tumor. With the intention to employ the knowledge of DC biology incancer treatments, I also explored the potential of DC targeting immunotherapies.Lastly, as an integral component of my exploration into DC biology, Iinvestigated how myeloid progenitors respond to both external and internalstress. Show less
Lei, X.; Groot, D.C. de; Welters, M.J.P.; Wit, T. de; Schrama, E.; Eenennaam, H. van; ... ; Xiao, Y.L. 2024
CD4(+) T cells can "help" or "license" conventional type 1 dendritic cells (cDC1s) to induce CD8(+) cytotoxic T lymphocyte (CTL) anticancer responses, as proven in mouse models. We recently... Show moreCD4(+) T cells can "help" or "license" conventional type 1 dendritic cells (cDC1s) to induce CD8(+) cytotoxic T lymphocyte (CTL) anticancer responses, as proven in mouse models. We recently identified cDC1s with a transcriptomic imprint of CD4(+) T-cell help, specifically in T-cell-infiltrated human cancers, and these cells were associated with a good prognosis and response to PD-1-targeting immunotherapy. Here, we delineate the mechanism of cDC1 licensing by CD4(+) T cells in humans. Activated CD4(+) T cells produce IFN beta via the STING pathway, which promotes MHC-I antigen (cross-)presentation by cDC1s and thereby improves their ability to induce CTL anticancer responses. In cooperation with CD40 ligand (L), IFN beta also optimizes the costimulatory and other functions of cDC1s required for CTL response induction. IFN-I-producing CD4(+) T cells are present in diverse T-cell-infiltrated cancers and likely deliver "help" signals to CTLs locally, according to their transcriptomic profile and colocalization with "helped/licensed" cDCs and tumor-reactive CD8(+) T cells. In agreement with this scenario, the presence of IFN-I-producing CD4(+) T cells in the TME is associated with overall survival and the response to PD-1 checkpoint blockade in cancer patients. Show less
Objective: To assess the efficacy and toxicity of proton radiotherapy in vestibular schwannoma. Study Design: Retrospective chart review and volumetric MRI-analyses. Setting: Tertiary referral... Show moreObjective: To assess the efficacy and toxicity of proton radiotherapy in vestibular schwannoma. Study Design: Retrospective chart review and volumetric MRI-analyses. Setting: Tertiary referral center. Patients: Vestibular schwannoma patients treated with protons between 2003 and 2018. Intervention: Proton radiotherapy. Main Outcome Measures: Tumor control was defined as not requiring salvage treatment. Progressive hearing loss was defined as a decrease in maximum speech discrimination score below the 95% critical difference in reference to the pretreatment score. Hearing assessment includes contralateral hearing and duration of follow-up. Dizziness and/or unsteadiness and facial and trigeminal nerve function were scored. Patients who had surgery prior to proton radiotherapy were separately assessed. Results: Of 221 included patients, 136 received single fraction and 85 fractionated proton radiotherapy. Actuarial 5-year local control rate was 96% (95% CI 90-98%). The median radiological follow-up was 4.5 years. Progressive postirradiation speech discrimination score loss occurred in 42% of patients with audiometric follow-up within a year. Facial paresis was found in 5% (usually mild), severe dizziness in 5%, and trigeminal neuralgia in 5% of patients receiving protons as primary treatment. Conclusions: Proton radiotherapy achieves high tumor control with modest side effects aside from hearing loss in vestibular schwannoma patients. Limited and heterogeneous outcome reporting hamper comparisons to the literature. Potential sequelae of radiation therapy impacting vestibular function, cognitive function, and quality of life warrant further evaluation. Subgroups that benefit most from proton radiotherapy should be identified to optimize allocation and counterbalance its costs. Show less
