Cancer immunotherapy: weak beats strong

Deppert, Wolfgang; Bruns, Michael

doi:10.18632/aging.101134

Cited by 5 publications

(6 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This most likely reflects that the NP-epitope in H8N8 cells is only weakly immunogenic in BALB/c mice (for possible explanations see Discussion). As our previous data had shown that a weak immune response, and thus the generation of low avidity CTLs, prevents rapid CTL exhaustion [ 3 , 5 ], we analyzed the effect of transfer of H8N8 specific CTLs into NP8 tumor mice irradiated with 4 Gy prior to transfer. Such treatment not only significantly prolonged the time for tumor outgrowth, but completely cured the animals (Figure 7B , lane 5).…”

Section: Resultsmentioning

confidence: 99%

“…We envisioned that the idea of “weak beats strong” regarding immunogenicity of T-cell epitopes in cancer immunotherapy [ 5 ] could be further exploited in combining immunization strategies with immune checkpoint blockade therapy. LCMV infection of NP8 tumor mice led to only transient tumor regression, and tumors re-grew already within the next three weeks [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Immunotherapy of WAP-TNP mice with early stage mammary gland tumors

Bruns

Deppert

2017

Oncotarget

Self Cite

View full text Add to dashboard Cite

The SV40 transgenic BALB/c mouse based WAP-T/WAP-TNP model for triple-negative breast cancer allows the analysis of parameters influencing immunotherapeutic approaches. Except for WAP-TNP tumors expressing the immune-dominant LCMV NP-epitope within SV40 T-antigen (T-AgNP) which is not expressed by T-Ag of WAP-T tumors, the tumors are extremely similar. Comparative anti-PD1/PD-L1 immunotherapy of WAP-T and WAP-TNP mice supported the hypothesis that the immunogenicity of tumor antigen T-cell epitopes strongly influences the success of immune checkpoint blockade therapy, with highly immunogenic T-cell epitopes favoring rapid CTL exhaustion. Here we analyzed the immune response in NP8 mice during early times of tumor development. LCMV infection of lactating NP8 mice induced lifelong tumor protection by memory CTLs. Immunization with LCMV after involution and appearance of T-AgNP expressing parity-induced tumor progenitor cells could not cure the mice, as memory CTLs became exhausted. However, immunization significantly prolonged the time of tumor outgrowth. Elimination of exhausted CTLs and of immunosuppressive cells by sub-lethal γ-irradiation, followed by adoptive transfer of NP-epitope specific CTLs into NP8 tumor mice with early lesions, completely prevented tumor outgrowth, when lymphocytes obtained after injection of weakly immunogenic NP8 tumor-derived cells into BALB/c mice were transferred. Transfer of lymphocytes obtained after infection of BALB/c mice with highly immunogenic LCMV into such mice delayed tumor outgrowth for a significant period, but could not prevent it. We conclude that eliminating exhausted CTLs and immune-suppressive cells followed by transfer or generation of low-avidity tumor antigen-specific CTLs might be a promising approach for curative tumor immunotherapy.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunotherapy of WAP-TNP mice with early stage mammary gland tumors

Bruns

Deppert

2017

Oncotarget

Self Cite

View full text Add to dashboard Cite

show abstract

“…There are also some interesting data indicatung the tumor microenvironment, the indole 2,3-dioxygenase, and finally mutational landscape, as biomarkers for predicting the response to immunotherapy (Ji et al, 2012;Holmgaard et al, 2013;Anagnostou et al, 2017;Maleki et al, 2017). It has been demonstrated that tumors with many somatic mutations due to mismatch-repair defects are more susceptible to the immune checkpoint blockade than tumors lacking this property (Le et al, 2015;Deppert & Bruns, 2016). Thus, immunogenicity of the tumor antigen T-cell epitopes may also be significant for treatment success or failure.…”

Section: Introductionmentioning

confidence: 99%

Intracellular Mechanisms of Tumor Cell Immunoresistance

et al. 2020

View full text Add to dashboard Cite

One of the main mechanisms for avoiding immune response by cancer cells is by inducing an immunosuppressive environment in the tumor, following the activation of immune checkpoints i.e. PD-1 or CTLA-4 receptor inhibitors on T lymphocytes. Inhibiting the interaction between PD-1 or CTLA-4 and their ligands (PD-L1, CD80, and CD85) leads to unblocking T-lymphocyte function, and thus destroying cancer cells. Certain intracellular signaling pathways are also involved in the development of tumor cell immunoresistance. Blocking the activation of immunosuppressive pathways may increase immunological anti-tumor control

show abstract

“…Studies showed that neutralizing inflammation induced by myeloid-derived immune-suppressive cells could inhibit tumor development 10,11 . On the other hand, recent studies also indicated that the boosting antitumor immune response would be a cure for certain cancer patients 12 . The antitumor immune response is controlled by several factors, including the immunogenicity feature of tumors, antigen-presenting intensity, immune cell infiltration, and immune cell activation and cytotoxicity 13,14 .…”

Section: Introductionmentioning

confidence: 99%

CD103⁺ Cell Growth Factor Flt3L Enhances the Efficacy of Immune Checkpoint Blockades in Murine Glioblastoma Model

et al. 2018

View full text Add to dashboard Cite

Glioblastoma is a lethal disease featuring a high proliferation of tumor cells, excessive angiogenesis, and heavy drug resistance. The overall survival of glioblastoma patients has been dismal, even with an intensive standard of care. Recent advances in immune checkpoint blockades are changing the treatment of cancers. However, the efficacy of immune checkpoint blockades in glioblastoma is still unclear. Here we investigated the roles of CD103+ cells in regulating the effect of immune checkpoint blockades in glioblastoma mouse models. Our findings indicated that the murine glioblastoma model was not sensitive to immune checkpoint blockades. Flt3L, a growth factor for CD103+ cells, could significantly increase the number of CD103+ dendritic cells in the murine glioblastoma model and, thus, sensitize murine glioblastoma to immune checkpoint blockades. Downstream analysis indicated that the Flt3L and immune checkpoint blockade combination increased the number of tumor-infiltrating CD8+ cells, decreased immune checkpoint expression, and therefore enhanced the antitumor immune response in the murine glioblastoma model. These findings suggested that Flt3L could enhance the efficacy of immune checkpoint blockades in glioblastoma via expanding CD103+ dendritic cells and downstream antitumor immune response.

show abstract

Cancer immunotherapy: weak beats strong

Cited by 5 publications

References 7 publications

Immunotherapy of WAP-TNP mice with early stage mammary gland tumors

Immunotherapy of WAP-TNP mice with early stage mammary gland tumors

Intracellular Mechanisms of Tumor Cell Immunoresistance

CD103⁺ Cell Growth Factor Flt3L Enhances the Efficacy of Immune Checkpoint Blockades in Murine Glioblastoma Model

Contact Info

Product

Resources

About

Cancer immunotherapy: weak beats strong

Cited by 5 publications

References 7 publications

Immunotherapy of WAP-TNP mice with early stage mammary gland tumors

Immunotherapy of WAP-TNP mice with early stage mammary gland tumors

Intracellular Mechanisms of Tumor Cell Immunoresistance

CD103+ Cell Growth Factor Flt3L Enhances the Efficacy of Immune Checkpoint Blockades in Murine Glioblastoma Model

Contact Info

Product

Resources

About

CD103⁺ Cell Growth Factor Flt3L Enhances the Efficacy of Immune Checkpoint Blockades in Murine Glioblastoma Model