TY - JOUR
T1 - A genetic screen to identify gain- And loss-of-function modifications that enhance T-cell infiltration into tumors
AU - Rogers, Laura M.
AU - Wang, Zhaoming
AU - Mott, Sarah L.
AU - Dupuy, Adam J.
AU - Weiner, George J.
N1 - Funding Information:
Research reported in this publication was supported by the Iowa/Mayo Lymphoma SPORE (P50 CA97274) and the NCI of the NIH under award numbers K22CA225786 and P30CA086862. Sequencing data presented herein were obtained at the Genomics Division of the Iowa Institute of Human Genetics, which is supported, in part, by the University of Iowa Carver College of Medicine and the Holden Comprehensive Cancer Center. Flow cytometry data presented herein were obtained at the Flow Cytometry Facility, which is a Carver College of Medicine/ Holden Comprehensive Cancer Center core research facility at the University of Iowa. The facility is funded through user fees and the generous financial support of the Carver College of Medicine, Holden Comprehensive Cancer Center, and Iowa City Veteran's Administration Medical Center and the NCI of the NIH under award number 1 S10 OD016199-01A1.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - T-cell-mediated cancer immunotherapies, including anti-PD-1 and T cells expressing chimeric antigen receptors (CAR-T cells), are becoming standard treatments for many cancer types. CAR-T therapy, in particular, has been successful in treating circulating, but not solid, tumors. One challenge limiting immunotherapy success is that tumors lacking T-cell infiltration do not respond to treatment. Therefore, one potential strategy to overcome resistance is to enhance the ability of T cells to traffic into tumors. Here, we describe an unbiased in vivo genetic screen approach utilizing the Sleeping Beauty mutagenesis system to identify candidate genes in T cells that might be modified to drive intratumoral T-cell accumulation. This screen identified over 400 candidate genes in three tumor models. These results indicated substantial variation in gene candidate selection, depending on the tumor model and whether or not mice were treated with anti-PD-1, yet some candidate genes were identified in all tumor models and with anti-PD-1 therapy. Inhibition of the most frequently mutated gene, Aak1, affected chemokine receptor expression and enhanced T-cell trafficking in vitro and in vivo. Screen candidates should be further validated as therapeutic targets, with particular relevance to enhancing infiltration of adoptively transferred T cells into solid tumors.
AB - T-cell-mediated cancer immunotherapies, including anti-PD-1 and T cells expressing chimeric antigen receptors (CAR-T cells), are becoming standard treatments for many cancer types. CAR-T therapy, in particular, has been successful in treating circulating, but not solid, tumors. One challenge limiting immunotherapy success is that tumors lacking T-cell infiltration do not respond to treatment. Therefore, one potential strategy to overcome resistance is to enhance the ability of T cells to traffic into tumors. Here, we describe an unbiased in vivo genetic screen approach utilizing the Sleeping Beauty mutagenesis system to identify candidate genes in T cells that might be modified to drive intratumoral T-cell accumulation. This screen identified over 400 candidate genes in three tumor models. These results indicated substantial variation in gene candidate selection, depending on the tumor model and whether or not mice were treated with anti-PD-1, yet some candidate genes were identified in all tumor models and with anti-PD-1 therapy. Inhibition of the most frequently mutated gene, Aak1, affected chemokine receptor expression and enhanced T-cell trafficking in vitro and in vivo. Screen candidates should be further validated as therapeutic targets, with particular relevance to enhancing infiltration of adoptively transferred T cells into solid tumors.
UR - http://www.scopus.com/inward/record.url?scp=85100406371&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100406371&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-20-0056
DO - 10.1158/2326-6066.CIR-20-0056
M3 - Article
C2 - 32611665
AN - SCOPUS:85100406371
VL - 8
SP - 1206
EP - 1214
JO - Cancer immunology research
JF - Cancer immunology research
SN - 2326-6066
IS - 9
ER -