AUTHOR=Vianzon Vianca V. , Hanson Rylee M. , Garg Ishita , Joseph Gwenyth J. , Rogers Laura M. 

TITLE=Rank aggregation of independent genetic screen results highlights new strategies for adoptive cellular transfer therapy of cancer

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1235131

DOI=10.3389/fimmu.2023.1235131

ISSN=1664-3224

ABSTRACT=<p>Efficient intratumoral infiltration of adoptively transferred cells is a significant barrier to effectively treating solid tumors with adoptive cellular transfer (ACT) therapies. Our recent forward genetic, whole-genome screen identified T cell-intrinsic gene candidates that may improve tumor infiltration of T cells. Here, results are combined with five independent genetic screens using rank aggregation to improve rigor. This resulted in a combined total of 1,523 candidate genes – including 1,464 genes not currently being evaluated as therapeutic targets - that may improve tumor infiltration of T cells. Gene set enrichment analysis of a published human dataset shows that these gene candidates are differentially expressed in tumor infiltrating compared to circulating T cells, supporting translational potential. Importantly, adoptive transfer of T cells overexpressing gain-of-function candidates (<italic>AAK1<sup>ΔN125</sup></italic>, <italic>SPRR1B</italic>, and <italic>EHHADH</italic>) into tumor-bearing mice resulted in increased T cell infiltration into tumors. These novel gene candidates may be considered as potential therapeutic candidates that can aid adoptive cellular therapy in improving T cell infiltration into solid tumors.</p>