In:
The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 1_Supplement ( 2018-05-01), p. 178.17-178.17
Abstract:
Cancer cell lines grown in vitro and implanted into mice are a centerpiece of preclinical modeling. However, tumor implantation is an in vivo vaccination event that can impact tumor growth. Checkpoint inhibitors targeting PD1 or CTLA4 interactions are effective at unleashing suppressed pre-existing immunity in murine models, but do not generate new immune responses. We hypothesized that tumor control by checkpoint inhibitor immunotherapies was dependent on pre-existing immunity generated at tumor implantation. Using cancer cells engineered to express model antigens, spontaneous tumor models with defined trackable antigens, or unmodified cancer cells, we demonstrate that tumor implantation results in initial T cell mediated immunity. As the tumors progress, these cells become undetectable in the periphery and accumulate in the tumor, but do not prevent tumor progression. While tumors respond to checkpoint inhibitors administered closely following implantation, delayed administration results in a loss of efficacy. This efficacy can be recovered by the addition of radiation therapy to checkpoint inhibitors, permitting cure of established murine tumors that are not controlled by either therapy alone. However, blocking the immune response at tumor implantation using a range of approaches results in a complete loss of efficacy of tumor control by all therapies based around checkpoint inhibitors. We demonstrate an approach to ‘silently’ establish tumors in mice to test therapies that can initiate de novo immunity to tumors. These data have significant implications for current clinical attempts to use checkpoint inhibitors, which may not be a solution for patients without pre-existing immunity to their tumor.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.200.Supp.178.17
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2018
detail.hit.zdb_id:
1475085-5
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