Tissue-specific properties of type 1 dendritic cells in lung cancer: implications for immunotherapy

Abstract

Checkpoint inhibitors have led to remarkable benefits in non-small cell lung cancer (NSCLC), yet response rates remain below expectations. High-dimensional analysis and mechanistic experiments in clinical samples and relevant NSCLC models uncovered the immune composition of lung cancer tissues, providing invaluable insights into the functional properties of tumor-infiltrating T cells and myeloid cells. Among myeloid cells, type 1 conventional dendritic cells (cDC1s) stand out for their unique ability to induce effector CD8 T cells against neoantigens and coordinate antitumoral immunity. Notably, lung resident cDC1 are particularly abundant and long-lived and express a unique tissue-specific gene program, underscoring their central role in lung immunity. Here, we discuss recent insights on the induction and regulation of antitumoral T cell responses in lung cancer, separating it from the tissue-agnostic knowledge generated from heterogeneous tumor models. We focus on the most recent studies dissecting functional states and spatial distribution of lung cDC1 across tumor stages and their impact on T cell responses to neoantigens. Finally, we highlight relevant gaps and emerging strategies to harness lung cDC1 immunostimulatory potential.

Keywords: Dendritic; Immunotherapy; Lung Cancer.

Figure 1. Experimental models to study the immune microenvironment of non-small cell lung cancer (NSCLC). Genetically engineered mouse models of NSCLC are driven by a Cre-inducible Kras activating mutations combined with p53 loss of function (KP), providing a robust system to control tumor initiation in situ. (a) The left panel shows a summary of the strategies used to investigate antitumoral CD8 responses by introducing exogenous antigens or increasing the tumor mutational burden. The main conceptual findings on the persistence/functional states/dominance/clonality and spatial organization of CD8 responses are depicted in the scheme. (b) The right panel depicts the composition and impact of myeloid cells in KP lung tumors. Diverse neutrophil states accumulate during progression, with divergent impacts on tumor progression. Commensal bacteria can activate myeloid subsets, contributing to tumor growth and immune modulation. Tissue-resident macrophages (TRMs) promote epithelial-mesenchymal transition and Treg-mediated immune evasion, while mono/derived macrophages drive the progression of established tumors. During aging, altered hematopoiesis supply the lung with suppressive myeloid cells.

Figure 2. Transcriptional identity of lung cDC1. Venn diagram showing the core genes shared between cDC1 isolated from lungs, spleen and liver and those selectively expressed in each of the indicated tissues. Transcriptomics data for cDC1 sorted from lung, liver and spleen were retrieved from the Immunological Genome Project website (https://www.immgen.org/) and analyzed in R (V.4.3.1). Normalized reads from each tissue were used to calculate the ratio between gene expression across tissues (lung vs spleen, lung vs liver and liver vs spleen). Genes with a ratio >5 in both comparisons were identified as tissue-exclusive. Shared genes have a ratio <2, between the two tissues but >5 with the third tissue. Only genes with more than 100 normalized reads were included in the analysis.

Figure 3. Spatiotemporal changes in cDC1 during non-small cell lung cancer (NSCLC) progression. The cartoon depicts cDC1 evolution during tumor progression, as it emerges from recent data. At tumor inception, the cDC1 compartment is enlarged and shows signs of activation as compared with resting lungs. cDC1 actively captures debris of dying cancer for cross-presentation and induction of antitumoral CD8 T cells and forms stable clusters with CD8⁺ T cells. In advanced tumors, cDCs acquire regulatory markers, fail to cross-present tumor antigens and inefficiently interact with T cells in lung tissues. Moreover, a suppressive environment is established in tumor-draining lymph nodes whereby Tregs blunt the ability of cDC1 to induce CD8 T cell priming.

Figure 4. Harnessing cDC1 for immunotherapy in experimental KP. Recent studies unveil the potential of dendritic cell (DC)-based therapies in lung tumors. Gungabeeson et al tested anti-CD40 as a single-agent therapy in the KP (Cre-inducible Kras activating mutations combined with p53 loss of function) model, demonstrating that tumor elimination can be achieved through the reprogramming of neutrophils, which acquire an interferon-stimulated gene (ISG) signature. This process is mediated by cDC1s and interferon-γ (IFN-γ). Schenkel et al demonstrated that a combination of FLT3 ligand (FLT3L) and anti-CD40 therapy effectively controls tumor progression by expanding a reservoir of TCF-1+CD8+ T cells. López et al showed that DC therapy enhances the diversity and magnitude of neoantigen-specific CD8+ T cells and delays the growth of ICB refractory lung tumors.