Tumor Patrol: Dendritic Cells in Anti-Tumor Immunity

In the last few decades, extensive research has shown that our immune system is not merely a bystander, but actively participates in recognizing and eliminating cancer cells. This knowledge has enabled researchers to harness different components of the immune system, involving both innate and adaptive immunity, to specifically target cancer cells.

 An effective immune response involves complex interactions between tumor cells and their microenvironment and the host’s immune system. Tumors overcome this immune challenge by subverting and/or developing counter-regulatory mechanisms to avoid immune recognition, a process regulated by dendritic cells (DCs). In this article, we summarize established concepts about DCs and discuss new insights from Pittet et al. (2023) about how DCs control immune responses in the tumor microenvironment (TME) and what implications this may have for cancer immunotherapy.

What are Dendritic Cells?

DCs are key regulators of the immune response by virtue of their antigen presenting abilities. DCs detect various pathogens and present these antigens to specific T cells. This leads to the activation of the T cell, triggering effector functions that aim to eliminate the pathogen. Not only can DCs modulate an immune response to foreign pathogens, but they can also induce tolerance to self-antigens, avoiding the unnecessary destruction of the host's own tissue (Mellman 2013). In this way, DCs play a key role in initiating antigen-specific responses and, therefore, act as a bridge between the innate and adaptive immune systems.

DCs can differentiate into conventional DCs (cDCs), plasmacytoid DCs (pDCs), or monocyte-derived DCs (MoDCs) (Mazzoccoli and Liu 2024). cDCs are the most well-characterized of the DC subtypes. They consist of cDC1 and cDC2 subsets — while the cDC1 subset primarily cross-presents antigens to activate cytotoxic CD8⁺ T cells, the cDC2 subset is known to regulate CD4⁺ T helper cell (Th1 and Th17) responses (Eisenbarth 2018).

The DC-Mediated Immune Response in Cancer

DCs play a vital role in regulating the antitumor response by infiltrating tumors, sampling antigens, and then migrating to the draining lymph node (LN) to present tumor antigens to naïve T cells, thus activating their antitumor functions (Wylie et al. 2019).

A recent paper discussed how high expression of cDC1 gene signatures in tumors correlates with improved patient survival. This is probably due to the ability of tumor-infiltrating cDC1s to produce chemokines such as CXCL9 and CXCL10 that activate CD8⁺ T cells present locally and potentiate antitumor responses.

In immunologically “hot” tumors like melanomas, characterized by increased immune infiltration and responsiveness to immunotherapy, the density of cDC2s intratumorally was found to be associated with high CD4⁺ T cell numbers, a minimal CD8⁺ T cell response, and improved responsiveness to anti-PD-1 therapy. However, this was only the case in tumors with low numbers of regulatory T cells.

Chemokine receptor 7⁺ (CCR7⁺) DCs derived from cDC1s or cDC2s have been shown to mold anti-tumor responses by populating the perivascular niche of the tumor stroma. Here, they express specific chemokines, such as CXCL16, that attract or retain activated antigen-specific T cells and promote their expansion in the TME. Additionally, CCR7⁺ DCs promote the differentiation of CD8⁺ T cells into effector cells. Overall, high levels of CCR7⁺ DCs in the tumor correlated with better treatment response and patient survival.

How Do Cancers Subvert DC-Mediated Immunity?

Cancers create a DC-suppressive milieu in the TME in multiple ways. One study showed that melanoma cells repressed Flt3 activation, which is required for DC differentiation and trafficking to the tumors. Indeed, adoptive transfer of DCs induced by Flt3 ligand (Flt3L) treatment led to an increased presence of DCs in the tumor and a better immune response (Spranger et al. 2015).

Cancers also maintain a “cold” TME, characterized by limited immune activity, by promoting mutations in key genes such as LKB1, PTEN, and IDH1 that impact different aspects of DC function, such as decreasing their ability to migrate and activate T cells, leading to a diminished response to immunotherapy.

Tumor cells also secrete a multitude of factors such as interleukin (IL)-10, IL-6, vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β) into the TME. Interleukins activate STAT3, which is a known inhibitor of DC maturation, while growth factors disrupt the differentiation of DCs from their progenitors.

Collectively, cancers evade DC-mediated immune responses by reshaping the TME to prevent the differentiation, activation, and infiltration of DCs into the tumor.

Leveraging DCs into Novel Therapies

The current goal to exploit DCs for cancer immunotherapy is twofold — to increase the number of DCs infiltrating the TME and to enhance the ability of DCs to activate T cell responses.

A therapeutic strategy known as DC vaccination has shown promise in the treatment of cancer. These vaccines seek to stimulate antigen-specific DC enrichment and elicit a long-lived CD8⁺ T cell response. For example, the FDA-approved vaccine, Provenge, uses the patient’s own DCs stimulated ex vivo with PAP, the antigen expressed by prostate cancer cells. When infused back into the patient, these DCs will present PAP, enabling them to activate antigen-specific T cells targeting the cancer. This approach has been shown to increase survival in prostate cancer (Cheever et al. 2011).

Another strategy employed to increase the activation of DCs is by using agonists. Flt3L vaccination, in combination with a TLR3 ligand, induced an increase in DC activation in non-Hodgkin’s lymphoma.

CD40 agonists are designed to mirror CD40L, which is expressed on activated T cells. These agonists trigger crosslinking and stimulation of CD40 receptors on DCs, leading to DC maturation and enhanced antigen presenting capabilities (Salomon et al. 2022). The success of CD40 agonism in activating DCs in pancreatic cancer has led to multiple clinical trials in gliomas, bladder cancer, and other solid tumors. Interestingly, combinatorial strategies using both vaccines and CD40 agonism have also yielded success, demonstrating that knowledge gleaned from DC function in the TME has translational benefits (Perez and De Palma 2019).

In conclusion, new evidence shows that DCs not only monitor and shape anti-tumor responses in lymph nodes but also reside in the TME and are indicators of treatment outcomes. These new insights into DC biology will allow us to harness their therapeutic potential to improve immunotherapies.