In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1697-1697
Abstract:
Approximately 20-40% of cancer patients who initially benefit from PD-1/L1 checkpoint blockade later develop progressive disease, which is associated with genetic and/or phenotypic changes in tumor cells that enable acquired resistance. Tumors from patients who have developed acquired resistance to checkpoint blockade (CPI-AR) typically demonstrate downregulation of specific antigens or proteins involved in antigen presentation on MHC class I, and dysregulation of interferon response pathways. With increasing CPI use across a large number of tumor types, the proportion of cancer patients with CPI-AR is increasing. Pre-clinical tumor models which mimic CPI-AR in humans are needed. We generated in vivo CPI-AR tumor models by serially passaging common CPI responsive murine syngeneic tumor cell lines (i.e. CT26) in vivo, followed by the excision and ex vivo expansion of the tumors that failed to respond to anti-PD1. This was repeated until passaged tumors no longer responded to anti-PD1 therapy. Transcriptomes of CT26 parental, CT26/CPI-AR, and B16.F10 melanoma (considered CPI primary resistant, CPI-PR) tumors were sequenced either under normal culture conditions or following 24 hour exposure to IFNg to assess interferon responsiveness. Here we present the genomic characterization of the CPI -PR and -AR models. Paradoxically, CPI-AR tumors maintain a state of type I/II IFN gene hyperactivation and increased expression of genes involved in MHC class I mediated antigen presentation/processing. Despite this transcriptional hyperactivity, CPI-AR tumor cells have a decreased capacity to translate and traffic these associated proteins to the cell membrane. Interestingly, upon challenge with IFNg, CPI-AR tumors down-regulate gene expression for PD-L1, TAP1, TAP2, β2M and other key pathways typically up-regulated by IFN stimulation. Collectively, the CPI-AR and -PR tumor models reflect many of the genomic and phenotypic changes reported in CPI-AR cancer patients. The CT26/CPI-AR tumors reproduce a state of IFN hypo-responsiveness and genetic/protein dysregulation. These clinically relevant models can be used to screen therapeutics that may translate to meaningful benefit for CPI-AR cancer patients. Citation Format: George J. Fromm, Danish Memon, Suresh de Silva, Kyung Jin Yoo, Kellsey Johannes, Casey Shuptrine, Jaya Miriyala, Arpita Patel, Fatima Rangwala, Zachary Opheim, Thuy-Ai Nguyen, Louis Gonzalez, Fatima Rangwala, Taylor H. Schreiber, Matthew D. Hellmann, Martin L. Miller, Taylor H. Schreiber. The development of an in vivo model of checkpoint acquired resistance, reveals a program of interferon hyperstimulation, resulting in dysregulation of MHC class I, protein translation/trafficking, and other unique pathways, that may be useful for guiding clinical strategy in patients with phenotypic similarities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1697.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2021-1697
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2021
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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