scholarly journals Role of Myeloid Cells in Oncolytic Reovirus-Based Cancer Therapy

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 654
Author(s):  
Vishnupriyan Kumar ◽  
Michael A. Giacomantonio ◽  
Shashi Gujar
Keyword(s):  
T Cell ◽  
Cancer Therapy ◽  
Critical Role ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Antitumor Effects ◽  
Cell Responses ◽  
Combination Strategies ◽  
Cell Immunity

Oncolytic reovirus preferentially targets and kills cancer cells via the process of oncolysis, and additionally drives clinically favorable antitumor T cell responses that form protective immunological memory against cancer relapse. This two-prong attack by reovirus on cancers constitutes the foundation of its use as an anticancer oncolytic agent. Unfortunately, the efficacy of these reovirus-driven antitumor effects is influenced by the highly suppressive tumor microenvironment (TME). In particular, the myeloid cell populations (e.g., myeloid-derived suppressive cells and tumor-associated macrophages) of highly immunosuppressive capacities within the TME not only affect oncolysis but also actively impair the functioning of reovirus-driven antitumor T cell immunity. Thus, myeloid cells within the TME play a critical role during the virotherapy, which, if properly understood, can identify novel therapeutic combination strategies potentiating the therapeutic efficacy of reovirus-based cancer therapy.

scholarly journals Innate cell microenvironments in lymph nodes shape the generation of T cell responses during type I inflammation

2021 ◽  
Vol 6 (56) ◽  
pp. eabb9435
Author(s):  
Joseph M. Leal ◽  
Jessica Y. Huang ◽  
Karan Kohli ◽  
Caleb Stoltzfus ◽  
Miranda R. Lyons-Cohen ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Critical Role ◽  
Myeloid Cell ◽  
T Cell Responses ◽  
Type I ◽  
Cell Responses ◽  
Inflammatory Monocytes ◽  
Cell Effector

Microanatomical organization of innate immune cells within lymph nodes (LNs) is critical for the generation of adaptive responses. In particular, steady-state LN-resident dendritic cells (Res cDCs) are strategically localized to intercept lymph-draining antigens. Whether myeloid cell organization changes during inflammation and how that might affect the generation of immune responses are unknown. Here, we report that during type I, but not type II, inflammation after adjuvant immunization or viral infection, antigen-presenting Res cDCs undergo CCR7-dependent intranodal repositioning from the LN periphery into the T cell zone (TZ) to elicit T cell priming. Concurrently, inflammatory monocytes infiltrate the LNs via local blood vessels, enter the TZ, and cooperate with Res cDCs by providing polarizing cytokines to optimize T cell effector differentiation. Monocyte infiltration is nonuniform across LNs, generating distinct microenvironments with varied local innate cell composition. These spatial microdomains are associated with divergent early T cell effector programming, indicating that innate microenvironments within LNs play a critical role in regulating the quality and heterogeneity of T cell responses. Together, our findings reveal that dynamic modulation of innate cell microenvironments during type I inflammation leads to optimized generation of adaptive immune responses to vaccines and infections.

scholarly journals DC-Based Vaccines for Cancer Immunotherapy

Vaccines ◽  
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.

scholarly journals The critical role of CD4+ T cells in PD-1 blockade against MHC-II–expressing tumors such as classic Hodgkin lymphoma

2020 ◽  
Vol 4 (17) ◽  
pp. 4069-4082
Author(s):  
Joji Nagasaki ◽  
Yosuke Togashi ◽  
Takeaki Sugawara ◽  
Makiko Itami ◽  
Nobuhiko Yamauchi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Cd4 T Cell ◽  
Antitumor Effects ◽  
Cell Axis ◽  
Mhc I ◽  
Mhc Ii

Abstract Classic Hodgkin lymphoma (cHL) responds markedly to PD-1 blockade therapy, and the clinical responses are reportedly dependent on expression of major histocompatibility complex class II (MHC-II). This dependence is different from other solid tumors, in which the MHC class I (MHC-I)/CD8+ T-cell axis plays a critical role. In this study, we investigated the role of the MHC-II/CD4+ T-cell axis in the antitumor effect of PD-1 blockade on cHL. In cHL, MHC-I expression was frequently lost, but MHC-II expression was maintained. CD4+ T cells highly infiltrated the tumor microenvironment of MHC-II–expressing cHL, regardless of MHC-I expression status. Consequently, CD4+ T-cell, but not CD8+ T-cell, infiltration was a good prognostic factor in cHL, and PD-1 blockade showed antitumor efficacy against MHC-II–expressing cHL associated with CD4+ T-cell infiltration. Murine lymphoma and solid tumor models revealed the critical role of antitumor effects mediated by CD4+ T cells: an anti-PD-1 monoclonal antibody exerted antitumor effects on MHC-I−MHC-II+ tumors but not on MHC-I−MHC-II− tumors, in a cytotoxic CD4+ T-cell–dependent manner. Furthermore, LAG-3, which reportedly binds to MHC-II, was highly expressed by tumor-infiltrating CD4+ T cells in MHC-II–expressing tumors. Therefore, the combination of LAG-3 blockade with PD-1 blockade showed a far stronger antitumor immunity compared with either treatment alone. We propose that PD-1 blockade therapies have antitumor effects on MHC-II–expressing tumors such as cHL that are mediated by cytotoxic CD4+ T cells and that LAG-3 could be a candidate for combination therapy with PD-1 blockade.

Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T cell responses

2016 ◽  
Vol 8 (334) ◽  
pp. 334ra52-334ra52 ◽  
Author(s):  
Marij J. Welters ◽  
Tetje C. van der Sluis ◽  
Hélène van Meir ◽  
Nikki M. Loof ◽  
Vanessa J. van Ham ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Cell ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
T Cell Responses ◽  
Mouse Tumor ◽  
Therapeutic Vaccination ◽  
Advanced Cervical Cancer ◽  
Hpv16 E6 ◽  
Cell Responses

Therapeutic vaccination with human papillomavirus type 16 synthetic long peptides (HPV16-SLPs) results in T cell–mediated regression of HPV16-induced premalignant lesions but fails to install clinically effective immunity in patients with HPV16-positive cervical cancer. We explored whether HPV16-SLP vaccination can be combined with standard carboplatin and paclitaxel chemotherapy to improve immunity and which time point would be optimal for vaccination. This was studied in the HPV16 E6/E7–positive TC-1 mouse tumor model and in patients with advanced cervical cancer. In mice and patients, the presence of a progressing tumor was associated with abnormal frequencies of circulating myeloid cells. Treatment of TC-1–bearing mice with chemotherapy and therapeutic vaccination resulted in superior survival and was directly related to a chemotherapy-mediated altered composition of the myeloid cell population in the blood and tumor. Chemotherapy had no effect on tumor-specific T cell responses. In advanced cervical cancer patients, carboplatin-paclitaxel also normalized the abnormal numbers of circulating myeloid cells, and this was associated with increased T cell reactivity to recall antigens. The effect was most pronounced starting 2 weeks after the second cycle of chemotherapy, providing an optimal immunological window for vaccination. This was validated with a single dose of HPV16-SLP vaccine given in this time window. The resulting proliferative HPV16-specific T cell responses were unusually strong and were retained after all cycles of chemotherapy. In conclusion, carboplatin-paclitaxel therapy fosters vigorous vaccine-induced T cell responses when vaccination is given after chemotherapy and has reset the tumor-induced abnormal myeloid cell composition to normal values.

scholarly journals Critical role of protein glycosylation in T cell immunity/autoimmunity

2010 ◽  
Vol 69 (Suppl 2) ◽  
pp. A71-A72 ◽  
Author(s):  
T G Szabo ◽  
R Palotai ◽  
P Antal ◽  
I Tokatly ◽  
L Tothfalusi ◽  
...  
Keyword(s):  
T Cell ◽  
Critical Role ◽  
Protein Glycosylation ◽  
T Cell Immunity ◽  
Cell Immunity

scholarly journals Critical Role of SAP in Progression and Reactivation but Not Maintenance of T Cell-Dependent Humoral Immunity

2013 ◽  
Vol 33 (6) ◽  
pp. 1223-1232 ◽  
Author(s):  
Ming-Chao Zhong ◽  
André Veillette
Keyword(s):  
T Cell ◽  
B Cell ◽  
Humoral Immunity ◽  
Critical Role ◽  
Lymphoproliferative Disease ◽  
Germinal Center Reaction ◽  
Cell Responses ◽  
Cell Immunity ◽  
B Cell Responses ◽  
Signaling Lymphocytic Activation Molecule

Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is a small adaptor molecule mutated in X-linked lymphoproliferative disease, a human immunodeficiency. SAP plays a critical role in the initiation of T cell-dependent B cell responses leading to germinal center reaction, the production of high-affinity antibodies, and B cell memory. However, whether SAP has a role in these responses beyond their initiation is not known. It is important to address this matter not only for mechanistic reasons but also because blockade of the SAP pathway is being contemplated as a means to treat autoimmune diseases in humans. Using an inducibly SAP deficient mouse, we found that SAP was required not only for the initiation but also for the progression of primary T cell-driven B cell responses to haptens. It was also necessary for the reactivation of T cell-dependent B cell immunity during secondary immune responses. These activities consistently correlated with the requirement of SAP for full expression of the lineage commitment factor Bcl-6 in follicular T helper (TFH) cells. However, once memory B cells and long-lived antibody-secreting cells were established, SAP became dispensable for maintaining T cell-dependent B cell responses. Thus, SAP is pivotal for nearly all phases, but not for maintenance, of T cell-driven B cell humoral immunity. These findings may have implications for the treatment of immune disorders by targeting the SAP pathway.

scholarly journals Myeloid Cells in the Tumor Microenvironment: Modulation of Tumor Angiogenesis and Tumor Inflammation

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Michael C. Schmid ◽  
Judith A. Varner
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Angiogenesis ◽  
Malignant Tumors ◽  
Critical Role ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Promote Tumor Growth ◽  
Bone Marrow Derived Cells

Myeloid cells are a heterogeneous population of bone marrow-derived cells that play a critical role during growth and metastasis of malignant tumors. Tumors exhibit significant myeloid cell infiltrates, which are actively recruited to the tumor microenvironment. Myeloid cells promote tumor growth by stimulating tumor angiogenesis, suppressing tumor immunity, and promoting metastasis to distinct sites. In this review, we discuss the role of myeloid cells in promoting tumor angiogenesis. Furthermore, we describe a subset of myeloid cells with immunosuppressive activity (known as myeloid-derived suppressor cells). Finally, we will comment on the mechanisms regulating myeloid cell recruitment to the tumor microenvironment and on the potential of myeloid cells as new targets for cancer therapy.

scholarly journals Dendritic Cells in HIV/SIV Prophylactic and Therapeutic Vaccination

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 24
Author(s):  
Eun-Ju Ko ◽  
Marjorie Robert-Guroff
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Critical Role ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Effector Cells ◽  
Cell Responses ◽  
Complex Interactions ◽  
Cell Immunity ◽  
Immunodeficiency Virus

Dendritic cells (DCs) are involved in human and simian immunodeficiency virus (HIV and SIV) pathogenesis but also play a critical role in orchestrating innate and adaptive vaccine-specific immune responses. Effective HIV/SIV vaccines require strong antigen-specific CD4 T cell responses, cytotoxic activity of CD8 T cells, and neutralizing/non-neutralizing antibody production at mucosal and systemic sites. To develop a protective HIV/SIV vaccine, vaccine regimens including DCs themselves, protein, DNA, mRNA, virus vectors, and various combinations have been evaluated in different animal and human models. Recent studies have shown that DCs enhanced prophylactic HIV/SIV vaccine efficacy by producing pro-inflammatory cytokines, improving T cell responses, and recruiting effector cells to target tissues. DCs are also targets for therapeutic HIV/SIV vaccines due to their ability to reverse latency, present antigen, and augment T and B cell immunity. Here, we review the complex interactions of DCs over the course of HIV/SIV prophylactic and therapeutic immunizations, providing new insights into development of advanced DC-targeted HIV/SIV vaccines.

scholarly journals Immune Suppression by Myeloid Cells in HIV Infection: New Targets for Immunotherapy

2014 ◽  
Vol 8 (1) ◽  
pp. 66-78 ◽  
Author(s):  
Vikram Mehraj ◽  
Mohammad-Ali Jenabian ◽  
Kishanda Vyboh ◽  
Jean-Pierre Routy
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
Cell Function ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Immune Dysfunction ◽  
Hiv Pathogenesis ◽  
Host Restriction

Over thirty years of extensive research has not yet solved the complexity of HIV pathogenesis leading to a continued need for a successful cure. Recent immunotherapy-based approaches are aimed at controlling the infection by reverting immune dysfunction. Comparatively less appreciated than the role of T cells in the context of HIV infection, the myeloid cells including macrophages monocytes, dendritic cells (DCs) and neutrophils contribute significantly to immune dysfunction. Host restriction factors are cellular proteins expressed in these cells which are circumvented by HIV. Guided by the recent literature, the role of myeloid cells in HIV infection will be discussed highlighting potential targets for immunotherapy. HIV infection, which is mainly characterized by CD4 T cell dysfunction, also manifests in a vicious cycle of events comprising of inflammation and immune activation. Targeting the interaction of programmed death-1 (PD-1), an important regulator of T cell function; with PD-L1 expressed mainly on myeloid cells could bring promising results. Macrophage functional polarization from pro-inflammatory M1 to anti-inflammatory M2 and vice versa has significant implications in viral pathogenesis. Neutrophils, recently discovered low density granular cells, myeloid derived suppressor cells (MDSCs) and yolk sac macrophages provide new avenues of research on HIV pathogenesis and persistence. Recent evidence has also shown significant implications of neutrophil extracellular traps (NETs), antimicrobial peptides and opsonizing antibodies. Further studies aimed to understand and modify myeloid cell restriction mechanisms have the potential to contribute in the future development of more effective anti-HIV interventions that may pave the way to viral eradication.

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