Plasmacytoid Dendritic Cells and Cancer Immunotherapy

Despite largely disappointing clinical trials of dendritic cell (DC)-based vaccines, recent studies have shown that DC-mediated cross-priming plays a critical role in generating anti-tumor CD8 T cell immunity and regulating anti-tumor efficacy of immunotherapies. These new findings thus support further development and refinement of DC-based vaccines as mono-immunotherapy or combinational immunotherapies. One exciting development is recent clinical studies with naturally circulating DCs including plasmacytoid DCs (pDCs). pDC vaccines were particularly intriguing, as pDCs are generally presumed to play a negative role in regulating T cell responses in tumors. Similarly, DC-derived exosomes (DCexos) have been heralded as cell-free therapeutic cancer vaccines that are potentially superior to DC vaccines in overcoming tumor-mediated immunosuppression, although DCexo clinical trials have not led to expected clinical outcomes. Using a pDC-targeted vaccine model, we have recently reported that pDCs required type 1 conventional DCs (cDC1s) for optimal cross-priming by transferring antigens through pDC-derived exosomes (pDCexos), which also cross-prime CD8 T cells in a bystander cDC-dependent manner. Thus, pDCexos could combine the advantages of both cDC1s and pDCs as cancer vaccines to achieve better anti-tumor efficacy. In this review, we will focus on the pDC-based cancer vaccines and discuss potential clinical application of pDCexos in cancer immunotherapy.

Download Full-text

DC-Derived Exosomes for Cancer Immunotherapy

Cancers ◽

10.3390/cancers13153667 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3667

Author(s):

Yi Yao ◽

Chunmei Fu ◽

Li Zhou ◽

Qing-Sheng Mi ◽

Aimin Jiang

Keyword(s):

Clinical Trials ◽

T Cell ◽

Cancer Immunotherapy ◽

Clinical Efficacy ◽

Cancer Vaccines ◽

Tumor Antigens ◽

Critical Role ◽

Promising Alternative ◽

Cell Immunity ◽

Cancer Immunotherapies

As the initiators of adaptive immune responses, DCs play a central role in regulating the balance between CD8 T cell immunity versus tolerance to tumor antigens. Exploiting their function to potentiate host anti-tumor immunity, DC-based vaccines have been one of most promising and widely used cancer immunotherapies. However, DC-based cancer vaccines have not achieved the promised success in clinical trials, with one of the major obstacles being tumor-mediated immunosuppression. A recent discovery on the critical role of type 1 conventional DCs (cDC1s) play in cross-priming tumor-specific CD8 T cells and determining the anti-tumor efficacy of cancer immunotherapies, however, has highlighted the need to further develop and refine DC-based vaccines either as monotherapies or in combination with other therapies. DC-derived exosomes (DCexos) have been heralded as a promising alternative to DC-based vaccines, as DCexos are more resistance to tumor-mediated suppression and DCexo vaccines have exhibited better anti-tumor efficacy in pre-clinical animal models. However, DCexo vaccines have only achieved limited clinical efficacy and failed to induce tumor-specific T cell responses in clinical trials. The lack of clinical efficacy might be partly due to the fact that all current clinical trials used peptide-loaded DCexos from monocyte-derived DCs. In this review, we will focus on the perspective of expanding current DCexo research to move DCexo cancer vaccines forward clinically to realize their potential in cancer immunotherapy.

Download Full-text

DC-Based Vaccines for Cancer Immunotherapy

Vaccines ◽

10.3390/vaccines8040706 ◽

2020 ◽

Vol 8 (4) ◽

pp. 706

Author(s):

Chunmei Fu ◽

Li Zhou ◽

Qing-Sheng Mi ◽

Aimin Jiang

Keyword(s):

Clinical Trials ◽

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cd8 T Cells ◽

Critical Role ◽

Cd8 T Cell ◽

T Cell Immunity ◽

Cell Responses ◽

Cell Immunity

As the sentinels of the immune system, dendritic cells (DCs) play a critical role in initiating and regulating antigen-specific immune responses. Cross-priming, a process that DCs activate CD8 T cells by cross-presenting exogenous antigens onto their MHCI (Major Histocompatibility Complex class I), plays a critical role in mediating CD8 T cell immunity as well as tolerance. Current DC vaccines have remained largely unsuccessful despite their ability to potentiate both effector and memory CD8 T cell responses. There are two major hurdles for the success of DC-based vaccines: tumor-mediated immunosuppression and the functional limitation of the commonly used monocyte-derived dendritic cells (MoDCs). Due to their resistance to tumor-mediated suppression as inert vesicles, DC-derived exosomes (DCexos) have garnered much interest as cell-free therapeutic agents. However, current DCexo clinical trials have shown limited clinical benefits and failed to generate antigen-specific T cell responses. Another exciting development is the use of naturally circulating DCs instead of in vitro cultured DCs, as clinical trials with both human blood cDC2s (type 2 conventional DCs) and plasmacytoid DCs (pDCs) have shown promising results. pDC vaccines were particularly encouraging, especially in light of promising data from a recent clinical trial using a human pDC cell line, despite pDCs being considered tolerogenic and playing a suppressive role in tumors. However, how pDCs generate anti-tumor CD8 T cell immunity remains poorly understood, thus hindering their clinical advance. Using a pDC-targeted vaccine model, we have recently reported that while pDC-targeted vaccines led to strong cross-priming and durable CD8 T cell immunity, cross-presenting pDCs required cDCs to achieve cross-priming in vivo by transferring antigens to cDCs. Antigen transfer from pDCs to bystander cDCs was mediated by pDC-derived exosomes (pDCexos), which similarly required cDCs for cross-priming of antigen-specific CD8 T cells. pDCexos thus represent a new addition in our arsenal of DC-based cancer vaccines that would potentially combine the advantage of pDCs and DCexos.

Download Full-text

Targeting monoamine oxidase A for T cell–based cancer immunotherapy

Science Immunology ◽

10.1126/sciimmunol.abh2383 ◽

2021 ◽

Vol 6 (59) ◽

pp. eabh2383

Author(s):

Xi Wang ◽

Bo Li ◽

Yu Jeong Kim ◽

Yu-Chen Wang ◽

Zhe Li ◽

...

Keyword(s):

T Cell ◽

Monoamine Oxidase ◽

Tumor Growth ◽

Cancer Immunotherapy ◽

Monoamine Oxidase A ◽

T Cell Immunity ◽

Dependent Manner ◽

Cell Immunity ◽

Mao A ◽

And Behavior

Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain, where it breaks down neurotransmitters and thereby influences mood and behavior. Small-molecule MAO inhibitors (MAOIs) have been developed and are clinically used for treating depression and other neurological disorders. However, the involvement of MAO-A in antitumor immunity has not been reported. Here, we observed induction of the Maoa gene in tumor-infiltrating immune cells. Maoa knockout mice exhibited enhanced antitumor T cell immunity and suppressed tumor growth. MAOI treatment significantly suppressed tumor growth in preclinical mouse syngeneic and human xenograft tumor models in a T cell–dependent manner. Combining MAOI and anti–PD-1 treatments generated synergistic tumor suppression effects. Clinical data correlation studies associated intratumoral MAOA expression with T cell dysfunction and decreased patient survival in a broad range of cancers. We further demonstrated that MAO-A restrains antitumor T cell immunity through controlling intratumoral T cell autocrine serotonin signaling. Together, these data identify MAO-A as an immune checkpoint and support repurposing MAOI antidepressants for cancer immunotherapy.

Download Full-text

Faculty Opinions recommendation of Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726542716.793524820 ◽

2016 ◽

Author(s):

Joyce Solheim

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Tumor Antigen ◽

Critical Role ◽

T Cell Immunity ◽

Cell Immunity ◽

Antigen Trafficking

Download Full-text

Uncovering the Tumor Antigen Landscape: What to Know about the Discovery Process

Cancers ◽

10.3390/cancers12061660 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1660

Author(s):

Sara Feola ◽

Jacopo Chiaro ◽

Beatriz Martins ◽

Vincenzo Cerullo

Keyword(s):

T Cell ◽

Cancer Immunotherapy ◽

Tumor Antigens ◽

T Cell Response ◽

Antigenic Peptides ◽

T Cell Epitopes ◽

Antigen Discovery ◽

Future Challenges ◽

Major Bottleneck ◽

Therapeutic Cancer Vaccines

According to the latest available data, cancer is the second leading cause of death, highlighting the need for novel cancer therapeutic approaches. In this context, immunotherapy is emerging as a reliable first-line treatment for many cancers, particularly metastatic melanoma. Indeed, cancer immunotherapy has attracted great interest following the recent clinical approval of antibodies targeting immune checkpoint molecules, such as PD-1, PD-L1, and CTLA-4, that release the brakes of the immune system, thus reviving a field otherwise poorly explored. Cancer immunotherapy mainly relies on the generation and stimulation of cytotoxic CD8 T lymphocytes (CTLs) within the tumor microenvironment (TME), priming T cells and establishing efficient and durable anti-tumor immunity. Therefore, there is a clear need to define and identify immunogenic T cell epitopes to use in therapeutic cancer vaccines. Naturally presented antigens in the human leucocyte antigen-1 (HLA-I) complex on the tumor surface are the main protagonists in evocating a specific anti-tumor CD8+ T cell response. However, the methodologies for their identification have been a major bottleneck for their reliable characterization. Consequently, the field of antigen discovery has yet to improve. The current review is intended to define what are today known as tumor antigens, with a main focus on CTL antigenic peptides. We also review the techniques developed and employed to date for antigen discovery, exploring both the direct elution of HLA-I peptides and the in silico prediction of epitopes. Finally, the last part of the review analyses the future challenges and direction of the antigen discovery field.

Download Full-text

Critical role for adaptive T cell immunity in experimental eosinophilic esophagitis in mice

Journal of Leukocyte Biology ◽

10.1189/jlb.1106653 ◽

2006 ◽

Vol 81 (4) ◽

pp. 916-924 ◽

Cited By ~ 113

Author(s):

Anil Mishra ◽

James Schlotman ◽

Meiqin Wang ◽

Marc E. Rothenberg

Keyword(s):

T Cell ◽

Eosinophilic Esophagitis ◽

Critical Role ◽

T Cell Immunity ◽

Cell Immunity

Download Full-text

Telomerase and CD4 T Cell Immunity in Cancer

Cancers ◽

10.3390/cancers12061687 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1687

Author(s):

Magalie Dosset ◽

Andrea Castro ◽

Hannah Carter ◽

Maurizio Zanetti

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Critical Role ◽

Tumor Formation ◽

T Cell Immunity ◽

Cd4 T Cell ◽

Current Status ◽

Mhc Ii ◽

Cell Immunity

Telomerase reverse transcriptase (TERT) is a conserved self-tumor antigen which is overexpressed in most tumors and plays a critical role in tumor formation and progression. As such, TERT is an antigen of great relevance to develop widely applicable immunotherapies. CD4 T cells play a major role in the anti-cancer response alone or with other effector cells such as CD8 T cells and NK cells. To date, efforts have been made to identify TERT peptides capable of stimulating CD4 T cells that are also able to bind diverse MHC-II alleles to ease immune status monitoring and immunotherapies. Here, we review the current status of TERT biology, TERT/MHC-II immunobiology, and past and current vaccine clinical trials. We propose that monitoring CD4 T cell immunity against TERT is a simple and direct way to assess immune surveillance in cancer patients and a new way to predict the response to immune checkpoint inhibitors (ICPi). Finally, we present the initial results of a systematic discovery of TERT peptides able to bind the most common HLA Class II alleles worldwide and show that the repertoire of MHC-II TERT peptides is wider than currently appreciated.

Download Full-text