In:
The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 244.7-244.7
Kurzfassung:
A significant number of metastatic melanoma patients have disease progression despite checkpoint inhibitor therapy. We lack salvage strategies for this population and a mechanistic understanding of checkpoint inhibitor refractory disease. Previously, we reported that patients with liver metastasis have worse response rate and survival than those without liver metastasis despite treatment with checkpoint immunotherapy, but how liver metastasis can influence the antitumor immune response in this context is unclear. We hypothesize that tumor antigen-specific tolerance can be induced in the context of liver metastasis, resulting in therapy resistance. In this study, we developed a syngeneic two-site tumor model in which tumor cells are injected simultaneously into a subcutaneous (SQ) site and into the liver or other organ sites of B6 mice to study the effects of the intrahepatic tumor on antitumor immunity at a distant site. We found that the presence of tumor or tumor antigen within the liver reduced systemic antigen-specific effector T cell function. Tetramer and sc-RNAseq studies suggest a liver and antigen-specific immunoregulatory process associated with the activation of regulatory T cells and the remodeling of innate immune cells. Importantly, this systemic dysfunctional immune state was not reversed by anti-PD-1 monotherapy but rather by deleting (anti-CTLA-4) or destabilizing (EZH2 inhibitor) intratumoral Tregs, suggesting a distinct regulatory mechanism contributing to anti-PD-1 resistance that could be overcome to achieve complete tumor regression at all sites. Our results reveal a novel mechanism of checkpoint inhibitor resistance and suggest a strategy to improve the outcome for patients with liver metastasis.
Materialart:
Online-Ressource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.204.Supp.244.7
Sprache:
Englisch
Verlag:
The American Association of Immunologists
Publikationsdatum:
2020
ZDB Id:
1475085-5
