scholarly journals T-Cell Responses in Merkel Cell Carcinoma: Implications for Improved Immune Checkpoint Blockade and Other Therapeutic Options

2021 ◽  
Vol 22 (16) ◽  
pp. 8679
Author(s):  
Laura Gehrcken ◽  
Tatjana Sauerer ◽  
Niels Schaft ◽  
Jan Dörrie
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
T Cell Responses ◽  
Therapeutic Options ◽  
Merkel Cell ◽  
Cell Responses

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with rising incidence and high mortality. Approximately 80% of the cases are caused by the human Merkel cell polyomavirus, while the remaining 20% are induced by UV light leading to mutations. The standard treatment of metastatic MCC is the use of anti-PD-1/-PD-L1-immune checkpoint inhibitors (ICI) such as Pembrolizumab or Avelumab, which in comparison with conventional chemotherapy show better overall response rates and longer duration of responses in patients. Nevertheless, 50% of the patients do not respond or develop ICI-induced, immune-related adverse events (irAEs), due to diverse mechanisms, such as down-regulation of MHC complexes or the induction of anti-inflammatory cytokines. Other immunotherapeutic options such as cytokines and pro-inflammatory agents or the use of therapeutic vaccination offer great ameliorations to ICI. Cytotoxic T-cells play a major role in the effectiveness of ICI, and tumour-infiltrating CD8+ T-cells and their phenotype contribute to the clinical outcome. This literature review presents a summary of current and future checkpoint inhibitor therapies in MCC and demonstrates alternative therapeutic options. Moreover, the importance of T-cell responses and their beneficial role in MCC treatment is discussed.

scholarly journals Viral and tumor antigen-specific CD8 T-cell responses in Merkel cell carcinoma

2019 ◽  
Vol 344 ◽  
pp. 103961 ◽  
Author(s):  
Mahtab Samimi ◽  
Houssem Benlalam ◽  
Pascal Aumond ◽  
Pauline Gaboriaud ◽  
Delphine Fradin ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Tumor Antigen ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Merkel Cell ◽  
Cell Responses

scholarly journals T-cell Responses to Oncogenic Merkel Cell Polyomavirus Proteins Distinguish Patients with Merkel Cell Carcinoma from Healthy Donors

2014 ◽  
Vol 20 (7) ◽  
pp. 1768-1778 ◽  
Author(s):  
Rikke Lyngaa ◽  
Natasja Wulff Pedersen ◽  
David Schrama ◽  
Charlotte Albæk Thrue ◽  
Dafina Ibrani ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
T Cell Responses ◽  
Merkel Cell Polyomavirus ◽  
Merkel Cell ◽  
Cell Responses ◽  
Healthy Donors

scholarly journals 266 PD-1 blockade and T cell responses in merkel cell carcinoma

2017 ◽  
Vol 137 (5) ◽  
pp. S45
Author(s):  
N.J. Miller ◽  
C. Church ◽  
S. Fling ◽  
R. Kulikauskas ◽  
N. Ramchurren ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
T Cell Responses ◽  
Merkel Cell ◽  
Cell Responses

scholarly journals Activation of CD8+ T Cell Responses after Melanoma Antigen Targeting to CD169+ Antigen Presenting Cells in Mice and Humans

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 183 ◽  
Author(s):  
Dieke van Dinther ◽  
Miguel Lopez Venegas ◽  
Henrike Veninga ◽  
Katarzyna Olesek ◽  
Leoni Hoogterp ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Significant Proportion ◽  
T Cell Responses ◽  
Melanoma Antigen ◽  
Cell Responses ◽  
Melanoma Antigens ◽  
Hla A2.1

The lack of tumor-reactive T cells is one reason why immune checkpoint inhibitor therapies still fail in a significant proportion of melanoma patients. A vaccination that induces melanoma-specific T cells could potentially enhance the efficacy of immune checkpoint inhibitors. Here, we describe a vaccination strategy in which melanoma antigens are targeted to mouse and human CD169 and thereby induce strong melanoma antigen-specific T cell responses. CD169 is a sialic acid receptor expressed on a subset of mouse splenic macrophages that captures antigen from the blood and transfers it to dendritic cells (DCs). In human and mouse spleen, we detected CD169+ cells at an equivalent location using immunofluorescence microscopy. Immunization with melanoma antigens conjugated to antibodies (Abs) specific for mouse CD169 efficiently induced gp100 and Trp2-specific T cell responses in mice. In HLA-A2.1 transgenic mice targeting of the human MART-1 peptide to CD169 induced strong MART-1-specific HLA-A2.1-restricted T cell responses. Human gp100 peptide conjugated to Abs specific for human CD169 bound to CD169-expressing monocyte-derived DCs (MoDCs) and resulted in activation of gp100-specific T cells. Together, these data indicate that Ab-mediated antigen targeting to CD169 is a potential strategy for the induction of melanoma-specific T cell responses in mice and in humans.

scholarly journals Tumor-Specific T Cells in Human Merkel Cell Carcinomas: A Possible Role for Tregs and T-Cell Exhaustion in Reducing T-Cell Responses

2013 ◽  
Vol 133 (7) ◽  
pp. 1879-1889 ◽  
Author(s):  
Mitra Dowlatshahi ◽  
Victor Huang ◽  
Ahmed E. Gehad ◽  
Ying Jiang ◽  
Adam Calarese ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
T Cell Exhaustion ◽  
Merkel Cell ◽  
Cell Exhaustion ◽  
Cell Responses

scholarly journals The role of dendritic cells for therapy of B-cell lymphoma with immune checkpoint inhibitors

2020 ◽  
Author(s):  
Anne Scheuerpflug ◽  
Fatima Ahmetlić ◽  
Vera Bauer ◽  
Tanja Riedel ◽  
Martin Röcken ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cell ◽  
Immune Checkpoint ◽  
Cell Lymphoma ◽  
T Cell Responses ◽  
B Cell Lymphoma ◽  
Cell Responses

Abstract Immune checkpoint blocking (ICB) is a promising new tool of cancer treatment. Yet, the underlying therapeutic mechanisms are not fully understood. Here we investigated the role of dendritic cells (DCs) for the therapeutic effect of ICB in a λ-MYC-transgenic mouse model of endogenously arising B-cell lymphoma. The growth of these tumors can be effectively delayed by antibodies against CTLA-4 and PD-1. Tumor-infiltrating DCs from mice having received therapy showed an upregulation of costimulatory molecules as well as an augmented IL-12/IL-10 ratio as compared to untreated controls. Both alterations seemed to be induced by interferon-γ (IFN-γ), which is upregulated in T cells and natural killer cells upon ICB. Furthermore, the enhanced IL-12/IL-10 ratio, which favors Th1-prone antitumor T-cell responses, was a consequence of direct interaction of ICB antibodies with DCs. Importantly, the capability of tumor-infiltrating DCs of stimulating peptide-specific or allogeneic T-cell responses in vitro was improved when DCs were derived from ICB-treated mice. The data indicate that ICB therapy is not only effective by directly activating T cells, but also by triggering a complex network, in which DCs play a pivotal role at the interface between innate and adaptive antitumor responses.

scholarly journals Functional analysis of peripheral and intratumoral neoantigen-specific TCRs identified in a patient with melanoma

2021 ◽  
Vol 9 (9) ◽  
pp. e002754
Author(s):  
Eva Bräunlein ◽  
Gaia Lupoli ◽  
Franziska Füchsl ◽  
Esam T Abualrous ◽  
Niklas de Andrade Krätzig ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Immune Checkpoint ◽  
T Cell Responses ◽  
Functional Avidity ◽  
Cell Responses

BackgroundNeoantigens derived from somatic mutations correlate with therapeutic responses mediated by treatment with immune checkpoint inhibitors. Neoantigens are therefore highly attractive targets for the development of therapeutic approaches in personalized medicine, although many aspects of their quality and associated immune responses are not yet well understood. In a case study of metastatic malignant melanoma, we aimed to perform an in-depth characterization of neoantigens and respective T-cell responses in the context of immune checkpoint modulation.MethodsThree neoantigens, which we identified either by immunopeptidomics or in silico prediction, were investigated using binding affinity analyses and structural simulations. We isolated seven T-cell receptors (TCRs) from the patient’s immune repertoire recognizing these antigens. TCRs were compared in vitro by multiparametric analyses including functional avidity, multicytokine secretion, and cross-reactivity screenings. A xenograft mouse model served to study in vivo functionality of selected TCRs. We investigated the patient’s TCR repertoire in blood and different tumor-related tissues over 3 years using TCR beta deep sequencing.ResultsSelected mutated peptide ligands with proven immunogenicity showed similar binding affinities to the human leukocyte antigen complex and comparable disparity to their wild-type counterparts in molecular dynamic simulations. Nevertheless, isolated TCRs recognizing these antigens demonstrated distinct patterns in functionality and frequency. TCRs with lower functional avidity showed at least equal antitumor immune responses in vivo. Moreover, they occurred at high frequencies and particularly demonstrated long-term persistence within tumor tissues, lymph nodes and various blood samples associated with a reduced activation pattern on primary in vitro stimulation.ConclusionsWe performed a so far unique fine characterization of neoantigen-specific T-cell responses revealing defined reactivity patterns of neoantigen-specific TCRs. Our data highlight qualitative differences of these TCRs associated with function and longevity of respective T cells. Such features need to be considered for further optimization of neoantigen targeting including adoptive T-cell therapies using TCR-transgenic T cells.

Sign in / Sign up

Export Citation Format

Share Document