Harnessing dendritic cells for pancreatic cancer immunotherapy: a novel promising approach

Abstract

In a recently published study in Science, Mahadevan et al. offer a promising breakthrough in cancer immunotherapy by elucidating the pivotal role of Type I conventional dendritic cells (cDC1s) in enhancing immune checkpoint blockade therapy (iCBT) in pancreatic ductal adenocarcinoma (PDAC).¹

DCs, as key orchestrators of immunity and tolerance, play a crucial role in cancer immunotherapy by presenting antigens to T cells and secreting cytokines. DCs comprise diverse subsets, each with distinct functions and antigen-presenting abilities. The migration of DCs to lymph nodes is crucial for T cell-antigen interaction. Specifically, cDC1s demonstrate superior migratory ability,⁴ excelling in cross-presentation, which firmly establishes them as vital antigen-presenting cells. cDC1s capture antigens from deceased tumor cells, transport them to draining lymph nodes, and present them to CD8+ T cells, initiating an anti-cancer immune response (Figure 1A). This process is considered foundational for inducing anti-cancer CD8+ T cells.

Moreover, cDC1s are rich in T-cell co-stimulatory factors.⁵ They modulate immune cell migration and recruit T cells in situ through various chemokine-receptor interactions. Additionally, cDC1s secrete cytokines that support the tumor immune microenvironment. Combining cDC1s with iCBT enhances anti-tumor responses in multiple ways. For example, cDC1s enhance anti-PD-1 therapy in an IL-12-dependent manner.⁵ Crosstalk between cDC1-secreted cytokines and those produced by CD8+ T cells is crucial for reactivating exhausted T cells and subsequent anti-tumor responses.⁵

Mahadevan et al. discover that during pancreatitis, cDC1s frequency increases while T cells are suppressed. Activated cDC1s present self-antigens, suppressing CD4⁺ and CD8⁺ T cell infiltration and mitigating autoimmune tissue destruction. In PDAC associated with pancreatitis (ptPDAC), activated cDC1s frequency increases without T cell suppression. Spatial proximity between cDC1s and CD4⁺ T cells increases, with most infiltrating CD4⁺ T cells being Tregs, TH2, and TH17 subsets. Activated DCs triggered a tolerogenic CD4+ T cell reaction, promoting tumor initiation. However, specific depletion of CD4⁺ T cells elicits a potent CD8⁺ cytotoxic T cell response and inhibits tumorigenesis. Inflammation in ptPDAC accelerates cancer progression but provides immune traits favorable for immunotherapy. A cDC1 vaccine loaded with PDAC antigens enhances iCBT efficacy, induces functional CD8+ T cell memory responses to prevent recurrence, and offers a target for improving PDAC treatment.

The study highlights the mechanisms through which cDC1s exert their effects including antigen presentation and cytotoxic T cell activation key processes for targeting and destroying cancer cells.¹ Enhancing cDC1 function or numbers in tumors could improve immunotherapeutic outcomes. A cDC1 vaccine broadens tumor antigen diversity, enhances antigen-presenting, and reshapes immune infiltration by recruiting more oligoclonal T-cell populations to target a wider range of tumor antigens. Adding iCBT removes PD-1/CLTA-4-mediated suppression on T cells, boosting tumor-specific clone trafficking and retention at the tumor site (Figure 1B,C).

The research conducted by Mahadevan et al. marks substantial progress in understanding PDAC immunotherapy. By emphasizing the role of cDC1s, the study enriches the understanding of tumor immunology and lays the groundwork for novel therapeutic strategies. However, further investigations are essential to ensure the safety and efficacy of these strategies in clinical trials. Deciphering the mechanisms underlying cDC1s and iCBT-mediated immunity will be critical for maximizing clinical benefits.

H.Z. drafted the manuscript, Y.W. drew the figure, and X.L. drafted and reviewed the manuscript. All the authors read and approved the final manuscript.

The authors declare no conflict of interest.

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