Reviewed by Susha Cheriyedath, M.Sc.

In a recent review published in the journal Immunity, a group of authors reviewed the role of dendritic cells (DCs) in mediating T-cell responses in cancer, focusing on their interactions at both priming and effector sites, and exploring their potential implications for innovative cancer immunotherapies.

Review: Dendritic cells as shepherds of T cell immunity in cancer. Image Credit: Juan Gaertner / Shutterstock

Background

Tumor antigenicity, stemming from mutations and abnormal protein alterations, forms complexes that T cells recognize as foreign. Despite the role of tumor mutational burden in immunotherapy response, DC gene signatures are more indicative of T cell inflammation in tumors. This highlights the critical role of antigen processing and presentation. Instead of just initial interactions, DCs consistently impact the cancer immunity cycle, especially within tumors, underscoring their potential in immunotherapy. Further research is essential to explore DC-T cell interactions in tumors and design targeted immunotherapies.

Origins, functions, and roles of DCs in immunity

Discovered approximately 50 years ago, DCs serve as the immune system's guardians, assessing tissue conditions and processing antigens for potential dangers. Based on the signals they receive, DCs can modulate T-cell responses, either fostering tolerance or triggering a range of immune responses.

Subsets and states of DCs

Recent ontogenic and transcriptomic studies have unveiled multiple DC subsets and states. The primary focus of many researchers is on classical or conventional Type 1 DCs (cDC1s) and conventional Type 2 DCs (cDC2s) found in secondary lymphoid organs and tumors. However, monocyte-derived DCs (MoDCs) and interferon-producing cells (IPCs), or plasmacytoid DCs (pDCs), are also significant. Each subset has its origins: both cDC1s and cDC2s arise from common myeloid progenitors, while MoDCs develop from circulating monocytes.

Migration and trafficking

DCs, originating from myeloid progenitor cells in the bone marrow, can adopt different activated states once in tumors. C-C Chemokine Receptor Type 7(CCR7) + DCs, for instance, can migrate to draining lymph nodes, initiating complex T cell responses. Factors affecting DC migration include inflammation, chemokine receptors, and interactions with other immune cells.

Antigen sampling and presentation

In non-lymphoid tissues, DCs employ scavenger receptors like Dendritic and Epithelial Cell-205 (CD205), Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (CD209), and C-Type Lectin Domain Family 9 Member A (CLEC9A) for antigen sampling. CLEC9A stands out for its potential in anti-tumor immunity, as it can activate specific signals that enhance antigen presentation to Cluster of Differentiation 8 (CD8) + T cells.

Activation and response to cues

DCs respond to pathogen-associated and damage-associated molecular patterns, as well as inflammatory cytokines. These cues may prompt CCR7-mediated cDC migration or enhance antigen presentation. Interestingly, the programs for T cell activation and migration seem to be controlled separately.

Beyond cDCs, the tumor environment contains MoDCs and IPCs. MoDCs, especially active during inflammatory responses, are derived from circulating monocytes. IPCs are known for their Type I Interferon (IFN-I) production, which can help activate cDCs in certain situations.

T cell priming by DC subsets

Migration of cDCs to Lymph Nodes (LNs)

Migratory cDCs, upon reaching the draining LNs, move to areas abundant in CCR7 ligands CCL19 and CCL21, which are consistently surveyed by naive CD4+ and CD8+ T cells.T cells, using the LN stromal cell network, efficiently scan cDCs for specific peptide-MHC ligands. Recognizing a peptide-MHC complex initiates a series of interactions and signals between T cells and DCs. Stable contacts between these cells lead to a fully active T-cell response. This mechanism has been studied extensively through imaging in both mouse models and in vivo situations.

Interactions in LNs

The organization of LNs ensures that antigen-specific T cells and DCs meet effectively. Initial antigen recognition dictates the stability of T cell-DC interactions, influencing the immune response; stable interactions foster immunity, whereas unstable ones result in tolerance.

T cell immunity in LNs and tumors

In LNs, migratory DCs coordinate T cell responses, enabling antigen transfer and optimized T cell activation. In tumors, different DC subsets influence the fate and response of T cells, with certain DCs aiding in anti-tumor responses.

Roles of DC subsets in tumor immunity

Different DC subsets play pivotal roles in priming tumor-specific T-cell responses. cDC1s are especially crucial for CD8+ T cell immunity against tumors. While the roles of various DC subsets and their contributions are yet to be fully understood, the nature of the tumor antigen and DC uptake mechanisms could influence the actions of these subsets.

Role of DCs in tumor immunity

Tumor-infiltrating DCs significantly influence anti-tumor immunity. Studies have shown the conservation of these cells in both mice and humans, emphasizing their importance in tumor studies. The presence of specific DCs, notably cDC1s, and cDC2s, within tumors is linked to better patient outcomes: cDC1s activate CD8+ T cells, cDC2s enhance CD4+ T cell functions in the right tumor setting, and CCR7+ DCs attract and bolster effector T cells, amplifying anti-tumor responses. Additionally, tumors with a higher abundance of intratumoral CCR7+ DCs generally signify better patient outcomes and improved immunotherapy responses. Understanding the function and interaction of these cells in tumors can provide crucial insights for cancer treatments.

Understanding DC impairment in tumor immune response

Genomic and transcriptomic studies have uncovered immune cell patterns related to tumor genotypes, particularly involving DCs and T cells. Certain oncogenic mutations appear to suppress DC infiltration, leading to "immune cold" tumor microenvironments (TMEs) that potentially contribute to immunotherapy resistance in cancers like colorectal, melanoma, and pancreatic. Specific mutations, such as Liver Kinase B1 (LKB1), Phosphatase and Tensin Homolog (PTEN), or Isocitrate Dehydrogenase (IDH1), seem to influence DC function, impacting immune responses. Additionally, factors like Interleukin-10 (IL-10), Interleukin-6 (IL-6), and Vascular Endothelial Growth Factor (VEGF), produced within the TME, suppress DC responses and foster tumor growth. These findings emphasize the pivotal role of DCs in anti-tumor immunity and the potential therapeutic implications of targeting their function.

Advancing DC-based cancer therapies

DCs play pivotal roles in the cancer immunity cycle, especially in priming anti-tumor T cells and in driving T cell differentiation. Their essential role in anti-tumor immunity makes them a promising therapeutic target, and efforts have spanned over two decades. Present therapeutic aspirations for DCs include increasing their abundance in tumors and LN and enhancing their immunogenic functions. While past DC-based vaccination strategies show mixed results, next-generation vaccines aim for heightened DC functionality. Cellular engineering advances, such as the lentivirus-encoded extracellular vesicle-internalizing receptor (EVIR), hold promise. Timing of treatment, leveraging factors like Fms-like Tyrosine Kinase 3 Ligand (Flt3L) and CD40 agonism, and insights from single-cell ribonucleic acid (RNA) sequencing also present new avenues for refining and improving DC-based cancer therapies.

Journal reference:

• Pittet et al., Dendritic cells as shepherds of T cell immunity in cancer, Immunity (2023), DOI- https://doi.org/10.1016/ j.immuni.2023.08.014,  https://www.sciencedirect.com/science/article/pii/S1074761323003709