AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML

Sayitoglu, E. C.; Luca, B. A.; Boss, A. P.; Thomas, B. C.; Freeborn, R. A.; Uyeda, M. J.; Chen, P. P.; Nakauchi, Y.; Waichler, C.; Lacayo, N. J.; Bacchetta, R.; Majeti, R.; Gentles, A. J.; Cepika, A.-M.; Roncarolo, M. G.

doi:10.1101/2023.09.21.558911

bioRxiv · 10.1101/2023.09.21.558911

AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML

Sayitoglu, E. C.·Luca, B. A.·Boss, A. P.·Thomas, B. C.·Freeborn, R. A.·Uyeda, M. J.·Chen, P. P.·Nakauchi, Y.·Waichler, C.·Lacayo, N. J.·Bacchetta, R.·Majeti, R.·Gentles, A. J.·Cepika, A.-M.·Roncarolo, M. G.

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Abstract

T cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples are resistant to killing by human engineered cytotoxic CD4+ T cells. Single-cell RNA-seq of primary AML samples and CD4+ T cells before and after their interaction uncovered transcriptional programs that correlate with AML sensitivity or resistance to CD4+ T cell killing. Resistance-associated AML programs were enriched in AML patients with poor survival, and killing-resistant AML cells did not engage T cells in vitro. Killing-sensitive AML potently activated T cells before being killed, and upregulated ICAM1, a key component of the immune synapse with T cells. Without ICAM1, killing-sensitive AML became resistant to killing to primary ex vivo-isolated CD8+ T cells in vitro, and engineered CD4+ T cells in vitro and in vivo. Thus, ICAM1 on AML acts as an immune trigger, allowing T cell killing, and could affect AML patient survival in vivo. SIGNIFICANCEAML is a common leukemia with sub-optimal outcomes. We show that AML transcriptional programs correlate with susceptibility to T cell killing. Killing resistance-associated AML programs are enriched in patients with poor survival. Killing-sensitive, but not resistant AML activate T cells and upregulate ICAM1 that binds to LFA-1 on T cells, allowing immune synapse formation which is critical for AML elimination. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC="FIGDIR/small/558911v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@84e2e1org.highwire.dtl.DTLVardef@4b2a40org.highwire.dtl.DTLVardef@c2d1f3org.highwire.dtl.DTLVardef@65db2c_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Sayitoglu, E. C., Luca, B. A., Boss, A. P., Thomas, B. C., Freeborn, R. A., Uyeda, M. J., Chen, P. P., Nakauchi, Y., Waichler, C., Lacayo, N. J., Bacchetta, R., Majeti, R., Gentles, A. J., Cepika, A.-M., Roncarolo, M. G.. 2023-09-23. AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML. https://doi.org/10.1101/2023.09.21.558911

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