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大学・研究所にある論文を検索できる 「Inactivation of the PD-1-dependent immunoregulation in mice exacerbates contact hypersensitivity resembling immune-related adverse events」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。
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Inactivation of the PD-1-dependent immunoregulation in mice exacerbates contact hypersensitivity resembling immune-related adverse events

Ashoori, Matin Dokht 京都大学 DOI:10.14989/doctor.k23105

2021.03.23

概要

The expression of PD-1 as a co-inhibitory receptor suppresses the effector T-cell responses and its blockade has been proven to be a durable strategy for strengthening immune responses in cancer treatment. This effective blockade of the PD-1 pathway provides a promising strategy of immunotherapy. Expanding the use of these immune checkpoint blockades in addition to unprecedented success in advanced cancer treatment, sometimes is along with detrimental disorder of immune-related adverse events (irAE). This irAE is reported in many patients who underwent PD-1 blockade therapy and among which dermatitis-like skin disease is the most frequent. Inflammatory tissue damage in irAE is progressive in some patients and in rare cases irAE reported critically dangerous in which cancer-immunotherapy was discontinued. Therefore, proactive management of irAE to prevent exacerbation is essential.

In this study, I evaluated that in what respect inactivation of the PD-1/PD-L1 pathway causes aggravated skin inflammation. To this end, an exacerbated oxazolone-induced contact hypersensitivity (CHS) by anti-PD-L1 mAb treatment has been used. This murine model consists of two distinct phases, a sensitization phase which begins by a topical application of oxazolone on the shaved abdomen, and an elicitation phase following frequent challenges with the same hapten on the ear. As a result, anti-PD-L1 mAb treatment in both phases caused a massive infiltration of CD8+ T cells into the inflamed tissue associated with significant ear edema. Consistent with that, an elevated number of CD8+ T cells and remarkable ear swelling has been observed in PD-1-/- mice.

Along with T cells, NK and dendritic cells were found to express a distinct level of PD-1 in the inflamed tissue. However only PD-1+ expressing T cells may have an indispensable role in exaggerating dermatitis following anti-PD-L1 mAb treatment. Multiple episodes of anti-PD-L1 mAb treatment in RAG2-/- mice did not enhance the ear inflammation.

The blockade of PD-L1 during the sensitization phase remarkably promoted the development of oxazolone-reactive effector T cells in draining Lymph nodes. Since an intensified CHS was guaranteed by the presence of oxazolone-specific T cells even though anti-PD-L1 mAb treatment was withheld during the elicitation phase.

Enhancement of local CD8+ T cell-dominant immune responses by PD-L1 blockade was correlated with the upregulation of CXCL9 and CXCL10 ligands of CXCR3. As neutralization of CXCR3 prevented the induction of vigorous dermatitis by anti-PD-L1 mAb. Non-hematopoietic CD45- cells identified as predominately responsible for upregulation of CXCL9 and CXCL10 in the inflamed ear following inactivation of the PD-1/PD-L1 pathway.

To generate skin inflammation similar to that observed in human dermal irAE a suboptimal dose of oxazolone has been used and as a result, neither a significant tissue swelling nor T cell accumulation in the ear was recognized. As opposed, immunopotentiation by anti-PD-L1 mAb helped to rise the subtle level of inflammation to visible dermatitis and increased CD4+ and CD8+ T cell numbers. Therefore, blockade of the PD-1 pathway can transform concealed skin irritation to significant dermatitis. Moreover, induction of T cell-dominant inflammation by anti-PD-L1 mAb was inhibited by the blockade of CXCR3.

In conclusion, the role of PD-1/PD-L1 inactivation in the regulation of skin inflammation was a matter of debate in this study. In this regard, I reproduced a CD8+ T cell-dominant form of cutaneous inflammation by the blockade of PD-L1 to evaluate the emergence mechanism of skin irAE. This exaggerated CHS shares common features with clinical observations in human dermal irAE. Results produced by this study can help a better management of skin irAE to improve the quality of immunotherapy in cancer patients.

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