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. 2023 Dec 5;14:8048. doi: 10.1038/s41467-023-43790-2

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 6 — a Normalized expression of a sensitizer gene signature (composed of top depleting genes in the BM arms of our screen) in pre-treatment leukemia samples from patients who are complete responders (CR) or non-responders (NR) to anti-hCD19 CAR-T therapy. The five number summaries of the CR and NR boxplots are 8.45, 9.09, 9.36, 9.72, 10.20, and 9.05, 9.47, 9.87, 10.08, 10.15, respectively. b Normalized expression of a JAK/STAT/MHC-I resistance signature in the same pre-treatment leukemia samples shown in (a). The five number summaries of the CR and NR boxplots are 8.77, 10.01, 10.65, 10.98, 11.62, and 9.87, 10.64, 11.24, 11.50, 11.78, respectively. For (a-b), the plots are graphed from minima to maxima and all data points are overlaid. c Normalized expression of the immune checkpoint blockade resistance-associated interferon-stimulated genes (ISG.RS) signature in B-ALL cells (after CAR-T failure) residing in expression cluster 2 or other cells. The ISG.RS signature is associated with poor outcomes in patients with large B-cell lymphoma treated with anti-CD19 CAR-T cells. A two-sided Wilcoxon rank-sum test was performed to compare the two distributions shown. An exact P value cannot be numerically determined due to ties in rank sum tests. A numerically approximate P value is shown. The plots are graphed in the Tukey method. The five-number summary for cluster 2 cells (left) is 0.036, 0.22, 0.28, 0.36, 0.57, and 0, 0.12, 0.18, 0.24, 0.42 for all other cells (right). d A final model for how high IFNγR/JAK/STAT signaling in tumor cells can promote resistance to CAR-T therapy via the upregulation of the NK and CD8⁺ T-cell inhibitory molecule Qa-1b, the murine homolog of HLA-E. Except where indicated, significance is determined using unpaired two-sided student’s t-tests with Bonferroni correction for multiple comparisons. Data are mean ± s.e.m. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.