cDC1 dysregulation in cancer: An opportunity for intervention

Conventional dendritic cells driven by the transcription factor Batf3 (cDC1 cells) are critical for the activation and maintenance of tumor-specific CD8+ T cells. In this issue of JEM, Lin et al. (https://doi.org/10.1084/jem.20190673) demonstrate systemic dysfunction of cDC1 cells in pancreatic cancer, which offers potential treatment strategies to expand the benefit of checkpoint blockade immunotherapy.

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453 Novel combination immunotherapy for boosting and priming immune responses in pancreatic cancer: strong anti-tumour effects with interleukin-15 and CD40 agonist treatment

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0453 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A480-A480

Author(s):

Jonas Van Audenaerde ◽

Elly Marcq ◽

Bianca von Scheidt ◽

Ashleigh Davey ◽

Amanda Oliver ◽

...

Keyword(s):

Pancreatic Cancer ◽

T Cells ◽

Dendritic Cells ◽

Natural Killer ◽

Mouse Models ◽

Cd8 T Cells ◽

Tumour Growth ◽

Immune Memory ◽

Combination Immunotherapy ◽

Interleukin 15

BackgroundWith the poorest 5-year survival of all cancers, improving treatment for pancreatic cancer is one of the biggest challenges in cancer research. In this era of combination immunotherapies, we sought to explore the potential of combining both priming and activation of the immune system. To achieve this, we combined a CD40 agonist with interleukin-15 and tested its potential in pancreatic cancer.MethodsTwo different mouse models of pancreatic cancer were used to assess the potential of this combination regimen. Therefore, effects on tumour growth kinetics and survival were charted. Differential effects on immune signatures was investigated using RNA sequencing. Functional immune subset involvement was tested using different immune depletion experiments and multicolour flow cytometry in different relevant immune sites. Immune memory was checked using re-challenge experiments.ResultsWe demonstrated profound reduction in tumour growth and increased survival of mice with the majority of mice being cured when both agents were combined, including an unprecedented dose reduction of CD40 agonist without losing any efficacy (fig 1). RNA sequencing analysis showed involvement of natural killer cell and T cell mediated anti-tumour responses and the importance of antigen-presenting cell pathways. This combination resulted in enhanced infiltration of tumours by both cytotoxic T cells and natural killer cells, as well as a striking increase in the ratio of CD8+ T cells over T regulatory cells. We also observed a significant increase in numbers of dendritic cells in tumour draining lymph nodes, particularly CD103+ dendritic cells with cross-presentation potential. A critical role for CD8+ T cells and involvement of natural killer cells in the anti-tumour effect was highlighted. Importantly, strong immune memory was established, with an increase in memory CD8+ T cells only when both interleukin-15 and the CD40 agonist were combined.Abstract 453 Figure 1Tumour kinetics and survival in Panc02 (left) and KPC (right) pancreatic cancer mouse modelsConclusionsWe demonstrated profound synergistic anti-tumour effects upon combination of CD40 agonist and interleukin-15 treatment in mouse models of pancreatic cancer. This preclinical data supports initiation of a first-in-human clinical trial with this combination immunotherapy strategy in pancreatic cancer.

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Transcription factor Etv6 regulates functional differentiation of cross-presenting classical dendritic cells

Journal of Experimental Medicine ◽

10.1084/jem.20172323 ◽

2018 ◽

Vol 215 (9) ◽

pp. 2265-2278 ◽

Cited By ~ 10

Author(s):

Colleen M. Lau ◽

Ioanna Tiniakou ◽

Oriana A. Perez ◽

Margaret E. Kirkling ◽

George S. Yap ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Transcription Factor ◽

T Cell ◽

Cd8 T Cells ◽

Functional Differentiation ◽

Specific Gene ◽

Hematopoietic Stem

An IRF8-dependent subset of conventional dendritic cells (cDCs), termed cDC1, effectively cross-primes CD8+ T cells and facilitates tumor-specific T cell responses. Etv6 is an ETS family transcription factor that controls hematopoietic stem and progenitor cell (HSPC) function and thrombopoiesis. We report that like HSPCs, cDCs express Etv6, but not its antagonist, ETS1, whereas interferon-producing plasmacytoid dendritic cells (pDCs) express both factors. Deletion of Etv6 in the bone marrow impaired the generation of cDC1-like cells in vitro and abolished the expression of signature marker CD8α on cDC1 in vivo. Moreover, Etv6-deficient primary cDC1 showed a partial reduction of cDC-specific and cDC1-specific gene expression and chromatin signatures and an aberrant up-regulation of pDC-specific signatures. Accordingly, DC-specific Etv6 deletion impaired CD8+ T cell cross-priming and the generation of tumor antigen–specific CD8+ T cells. Thus, Etv6 optimizes the resolution of cDC1 and pDC expression programs and the functional fitness of cDC1, thereby facilitating T cell cross-priming and tumor-specific responses.

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Skin dendritic cells in melanoma are key for successful checkpoint blockade therapy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000832 ◽

2021 ◽

Vol 9 (1) ◽

pp. e000832

Author(s):

Anastasia Prokopi ◽

Christoph H Tripp ◽

Bart Tummers ◽

Florian Hornsteiner ◽

Sarah Spoeck ◽

...

Keyword(s):

Flow Cytometry ◽

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Tumor Growth ◽

Tumor Progression ◽

Cd8 T Cells ◽

Checkpoint Blockade ◽

Tumor Stages ◽

Tumor Immunogenicity

BackgroundImmunotherapy with checkpoint inhibitors has shown impressive results in patients with melanoma, but still many do not benefit from this line of treatment. A lack of tumor-infiltrating T cells is a common reason for therapy failure but also a loss of intratumoral dendritic cells (DCs) has been described.MethodsWe used the transgenic tg(Grm1)EPv melanoma mouse strain that develops spontaneous, slow-growing tumors to perform immunological analysis during tumor progression. With flow cytometry, the frequencies of DCs and T cells at different tumor stages and the expression of the inhibitory molecules programmed cell death protein-1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) on T cells were analyzed. This was complemented with RNA-sequencing (RNA-seq) and real-time quantitative PCR (RT-qPCR) analysis to investigate the immune status of the tumors. To boost DC numbers and function, we administered Fms-related tyrosine 3 ligand (Flt3L) plus an adjuvant mix of polyI:C and anti-CD40. To enhance T cell function, we tested several checkpoint blockade antibodies. Immunological alterations were characterized in tumor and tumor-draining lymph nodes (LNs) by flow cytometry, CyTOF, microarray and RT-qPCR to understand how immune cells can control tumor growth. The specific role of migratory skin DCs was investigated by coculture of sorted DC subsets with melanoma-specific CD8+ T cells.ResultsOur study revealed that tumor progression is characterized by upregulation of checkpoint molecules and a gradual loss of the dermal conventional DC (cDC) 2 subset. Monotherapy with checkpoint blockade could not restore antitumor immunity, whereas boosting DC numbers and activation increased tumor immunogenicity. This was reflected by higher numbers of activated cDC1 and cDC2 as well as CD4+ and CD8+ T cells in treated tumors. At the same time, the DC boost approach reinforced migratory dermal DC subsets to prime gp100-specific CD8+ T cells in tumor-draining LNs that expressed PD-1/TIM-3 and produced interferon γ (IFNγ)/tumor necrosis factor α (TNFα). As a consequence, the combination of the DC boost with antibodies against PD-1 and TIM-3 released the brake from T cells, leading to improved function within the tumors and delayed tumor growth.ConclusionsOur results set forth the importance of skin DC in cancer immunotherapy, and demonstrates that restoring DC function is key to enhancing tumor immunogenicity and subsequently responsiveness to checkpoint blockade therapy.

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Radiation combines with immune checkpoint blockade to enhance T cell priming in a murine model of poorly immunogenic pancreatic cancer

Open Biology ◽

10.1098/rsob.210245 ◽

2021 ◽

Vol 11 (11) ◽

Author(s):

Courtney T. Stump ◽

Kevin Roehle ◽

Nataly Manjarrez Orduno ◽

Stephanie K. Dougan

Keyword(s):

Pancreatic Cancer ◽

T Cells ◽

Cd8 T Cells ◽

Immune Checkpoint ◽

Stereotactic Body Radiation Therapy ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Growth Delay ◽

T Cell Priming ◽

Effects Of Radiation

Radiation has been a pillar of cancer therapy for decades. The effects of radiation on the anti-tumour immune response are variable across studies and have not been explicitly defined in poorly immunogenic tumour types. Here, we employed combination checkpoint blockade immunotherapy with stereotactic body radiation therapy and examined the effect on tumour growth and immune infiltrates in subcutaneous and orthotopic mouse models of pancreatic cancer. Although immune checkpoint blockade and radiation were ineffective alone, their combination produced a modest growth delay in both irradiated and non-irradiated tumours that corresponded with significant increases in CD8+ T cells, CD4+ T cells and tumour-specific T cells as identified by IFNγ ELISpot. We conclude that radiation enhances priming of tumour-specific T cells in poorly immunogenic tumours and that the frequency of these T cells can be further increased by combination with immune checkpoint blockade.

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