Cancer cell-intrinsic resistance to BiTE therapy is mediated by loss of CD58 costimulation and modulation of the extrinsic apoptotic pathway

• DOI: 10.1136/jitc-2021-004348
• Publication Date: 2022-03-16T16:10:39Z
• Authors: Ye Shen; Jason S Eng; Flordeliza Fajardo; Lingming Liang; Cong Li; Patrick Collins; Donato Tedesco; Olivier Nolan-Ste...
• Keywords: Cancer Immunotherapy; CD80; CD86

Bispecific T-cell engager (BiTE) molecules induce redirected lysis of cancer cells by T and are an emerging modality for solid tumor immunotherapy. While signs clinical activity have been demonstrated, efficacy engagers (TCEs) in tumors settings, molecular determinants response, underlying mechanisms resistance to BiTE therapy require more investigation.To uncover cell-intrinsic genetic modifiers TCE-mediated cytotoxicity, we performed genome-wide CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) loss-of-function CRISPRa (CRISPR activation) gain-of-function screens using TCEs against two distinct tumor-associated antigens (TAAs). By vitro cytotoxicity assays vivo studies, validated the roles common pathways identified our screen, costimulation pathway apoptosis pathway, as key activity.Our uncovered TAAs-independent genes with functions autophagy, costimulation, chromatin remodeling, cytokine signaling that altered responsiveness BiTE-mediated killing. Notably, loss CD58 (the ligand CD2 costimulatory receptor), a gene frequently cancer, led decreased activation antitumor vivo. Moreover, effects were synergistically compounded concurrent CD80/CD86 (ligands CD28 whereas joint additively enhanced killing, indicating non-redundant between pathways. Additionally, CFLAR (Caspase-8 FADD Like Apoptosis Regulator), BCL2L1, BID (BH3 Interacting Domain Death Agonist) induced profound changes sensitivity TCEs, regulators apoptosis, which impact therapy.This study demonstrates alterations central carcinogenesis commonly detected samples lead significant modulation vivo, findings relevance better understanding patient responses novel combinations enhance TCE efficacy.