Frontiers in Immunology (Dec 2023)
Rank aggregation of independent genetic screen results highlights new strategies for adoptive cellular transfer therapy of cancer
Abstract
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 (AAK1ΔN125, SPRR1B, and EHHADH) 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.
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