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Proximity-dependent labeling identifies dendritic cells that prime the antitumor CD4+ T cell response

ABSTRACT: Dendritic cells (DCs) are uniquely capable of transporting tumoral antigens to tumor-draining lymph nodes (tdLNs), and also interact with effector T cells within the tumors themselves, mediating both natural antitumor immunity and the response to checkpoint blockade immunotherapy. Using LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts)-based single-cell transcriptomics, we identify individual DCs capable of presenting antigen to CD4+ T cells in the tdLN as well as inside tumors. These represent only a fraction of all DCs present and display a distinctive activated phenotype that in the LN includes production of cytokine IL-27, required for efficient T cell priming and tumor rejection. Tumor progression results in loss of effective priming of naïve CD4+ T cells, downstream of transcriptional changes in DCs that are manifested already when they arrive at the tdLN, which can be rescued by CTLA4 checkpoint blockade.

ORGANISM(S): Mus musculus

PROVIDER: GSE275471 | GEO | 2024/10/04

REPOSITORIES: GEO

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Project description:Background: While much progress has been accomplished in the understanding of radiation-induced immune effects in tumors, little is known regarding the mechanisms involved at the tumor draining lymph node (TDLN) level following tumor irradiation. The objective of this retrospective study was to assess the immune and biological changes arising in TDLN upon concurrent chemoradiotherapy of primary non-small cell lung cancer (NSCLC) tumors. Methods: Patients with proved localized (cN0M0) NSCLC, treated by radical surgery plus lymph node dissection with (CRT+) or without (CRT-) neoadjuvant chemoradiotherapy, whereby radiotherapy was targeted on the primary tumor with no significant incidental irradiation of the TDLN station (stations XI or X), were identified. Bulk RNA-Seq of TDLNs was performed and data were analyzed based on differential gene expression (DEG) and gene sets enrichment. Results: Sixteen patients were included and 25 TDLNs were analyzed: 6 patients in the CRT+ group (12 samples) and 10 patients in the CRT- group (13 samples). Overall, 1001 genes were differentially expressed between the two groups (CRT+ and CRT-). Analysis with g-profiler revealed that gene sets associated with antitumor immune response, inflammatory response, hypoxia, angiogenesis, epithelial mesenchymal transition and extra-cellular matrix remodeling were enriched in the CRT+ group, whereas only gene sets associated with B cells and B-cell receptor signaling were enriched in the CRT- group. Unsupervised dimensionality reduction identified two clusters of TDLNs from CRT+ patients, of which one cluster (cluster 1) exhibited higher expression of pathways identified as enriched in the overall CRT+ group in comparison to the CRT- group. In CRT+ cluster 1, 3 out of 3 patients had pathological complete response (pCR) or major complete response (MPR) to neoadjuvant CRT, whereas only 1 out of 3 patients in the other CRT+ cluster (cluster 2) experienced MPR and none exhibited pCR. Finally, pathway comparison to published data from pre-metastatic TDLNs uncovered similarities with CRT+ cluster 1. Conclusion: Neoadjuvant concurrent chemoradiotherapy of the primary tumor in N0 NSCLC patients is associated with distinct microenvironment and immunological patterns in TDLNs as compared to TDLNs from patients with non-irradiated tumors. Our data are in line with studies showing superiority of lymph node sparing irradiation of the primary tumor in the induction of systemic antitumor immunity.

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Proximity-dependent labeling identifies dendritic cells that prime the antitumor CD4+ T cell response

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