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Background Recent studies have shown that high numbers of Vδ1+ γδ T cells within the tumors are strongly associated with longer survival in patients of colorectal, non small-cell lung and triple-negative breast cancers. 1–3 Tumor cell recognition by Vδ1+ γδ T cells is distinct from the conventional αβ T cells4–6 and does not involve major histocompatibility complex (MHC) restrictions. Human Vδ1+ γδ T cells constitute up to 0.62% of total circulating CD3+ T cells in adults.7 Once activated, these cells undergo rapid expansion and form up to 30% of total tumor-infiltrating T cells during disease onset.8 Activated Vδ1+ γδ T cells produce large quantities of cytokines and chemokines to modulate other tumor-infiltrating immune cells 8 for eradication of haematological and solid tumors including tumors with MHC class I deficiencies that are capable to evade CD8+ T cell immunosurveillance.9–11 These unique properties make Vδ1+ γδ T cells an attractive candidate for tumor immunotherapy development. Nonetheless, a subset of tumor cells can gain resistance against Vδ1+ γδ T cell-mediated killing via unknown mechanisms.Methods To address this problem, we conducted genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 loss-of-function screens on human colorectal cancer (CRC) and acute myeloid leukemia (AML) under the immune pressure of human Vδ1+ γδ T cells using our established protocol. 12 Results Our screens identified novel targets in tumor cells that are involved in promoting immune evasion from Vδ1+ γδ T cell-mediated killing including genes associated with cytokine signalling pathway such as interferon-gamma receptor 1 (IFNGR1), IFNGR2, Janus kinase 1 (JAK1), JAK2, tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), TNFRSF1B and signal transducer and activator of transcription 1 (STAT1). Further, these screens identified other genes such as calreticulin (CALR) and intercellular adhesion molecule 1 (ICAM1) that can promote tumor immune evasion from Vδ1+ γδ T cell-mediated killing when knocked out from tumor cells.Conclusions As the molecular mechanisms of tumor cell resistance to Vδ1+ γδ T cell-mediated killing are elucidated, actionable strategies to prevent them may be derived to improve clinical outcomes for cancer patients.References Mikulak J, et al. NKp46-expressing human gut-resident intraepithelial Vdelta1 T cell subpopulation exhibits high antitumor activity against colorectal cancer. JCI Insight 2019;4:e125884.Wu Y, et al. An innate-like Vδ1+ γδ T cell compartment in the human breast is associated with remission in triple-negative breast cancer. Science Translational Medicine 2019;11:eaax9364.Wu Y, et al. A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer. Nature Cancer 2022;3:696-709.Chan KF, et al. Divergent T-cell receptor recognition modes of a HLA-I restricted extended tumour-associated peptide. Nat Commun 2018;9:1026.Zhao RY, et al. A novel HLA-B18 restricted CD8+ T cell epitope is efficiently cross-presented by dendritic cells from soluble tumor antigen. PLoS One 2012;7:e44707.Djajawi TM, et al. PRMT1 acts as a suppressor of MHC-I and anti-tumor immunity. Cell Reports 2024;43.Chan KF, et al. 442-P Characterizing human Vδ1+ and Vδ2+ γδ T cells for tumor immunotherapy development. Journal for ImmunoTherapy of Cancer 2023;11:A1800-A1800.Chan KF, et al. Gamma-delta T cells in the tumor microenvironment - interactions with other immune cells. Front Immunol 2022;13:894315.de Vries NL, et al. Gamma-delta T cells are effectors of immunotherapy in cancers with HLA class I defects. Nature 2023;613:743-750.Rancan C, et al. Exhausted intratumoral Vdelta2(-) gammadelta T cells in human kidney cancer retain effector function. Nat Immunol 2023;24:612-624.Davies D, et al. PD-1 defines a distinct, functional, tissue-adapted state in Vdelta1(+) T cells with implications for cancer immunotherapy. Nat Cancer 2024;5:420-432.Chan KF, et al. 431 Tumor immune evasion under Vδ2+ γδ T cell immune pressure. Journal for ImmunoTherapy of Cancer 2024;12:A490-A490.Ethics Approval ‘This study was approved by Australian Red Cross for the isolation of human Vδ1+ γδ T cells from healthy donors’ peripheral blood mononuclear cells, agreement number: 21-07VIC-09.’