Hypoxia-inducible factor activity promotes antitumor effector function and tissue residency by CD8+ T cells
Ilkka Liikanen, Colette Lauhan, Sara Quon, Kyla Omilusik, Anthony T. Phan, Laura Barceló Bartrolí, Amir Ferry, John Goulding, Joyce Chen, James P. Scott-Browne, Jason T. Yustein, Nicole E. Scharping, Deborah A. Witherden, Ananda W. Goldrath
Ilkka Liikanen, Colette Lauhan, Sara Quon, Kyla Omilusik, Anthony T. Phan, Laura Barceló Bartrolí, Amir Ferry, John Goulding, Joyce Chen, James P. Scott-Browne, Jason T. Yustein, Nicole E. Scharping, Deborah A. Witherden, Ananda W. Goldrath
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Research Article Immunology

Hypoxia-inducible factor activity promotes antitumor effector function and tissue residency by CD8+ T cells

Abstract

Adoptive T cell therapies (ACTs) hold great promise in cancer treatment, but low overall response rates in patients with solid tumors underscore remaining challenges in realizing the potential of this cellular immunotherapy approach. Promoting CD8+ T cell adaptation to tissue residency represents an underutilized but promising strategy to improve tumor-infiltrating lymphocyte (TIL) function. Here, we report that deletion of the HIF negative regulator von Hippel-Lindau (VHL) in CD8+ T cells induced HIF-1α/HIF-2α–dependent differentiation of tissue-resident memory–like (Trm-like) TILs in mouse models of malignancy. VHL-deficient TILs accumulated in tumors and exhibited a core Trm signature despite an exhaustion-associated phenotype, which led to retained polyfunctionality and response to αPD-1 immunotherapy, resulting in tumor eradication and protective tissue-resident memory. VHL deficiency similarly facilitated enhanced accumulation of chimeric antigen receptor (CAR) T cells with a Trm-like phenotype in tumors. Thus, HIF activity in CD8+ TILs promotes accumulation and antitumor activity, providing a new strategy to enhance the efficacy of ACTs.

Authors

Ilkka Liikanen, Colette Lauhan, Sara Quon, Kyla Omilusik, Anthony T. Phan, Laura Barceló Bartrolí, Amir Ferry, John Goulding, Joyce Chen, James P. Scott-Browne, Jason T. Yustein, Nicole E. Scharping, Deborah A. Witherden, Ananda W. Goldrath

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Figure 5

Expression of the Trm and T cell exhaustion gene expression signatures by VHL-deficient P14 TILs.

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Expression of the Trm and T cell exhaustion gene expression signatures b...
(A) Relative gene expression by VHL-KO and WT day 11 P14 TILs. Red and black denote an increase of 1.5-fold or greater in expression by VHL-KO over WT TILs or vice versa, respectively. (B and E) Changes in gene expression between VHL-KO and WT P14 for day 7 CD103+ TILs, days 7 and 11 bulk TILs, and day 7 spleen. (C) Volcano plots showing gene expression enrichment for Trm, TE, LLEC, and Tem signature genes from published datasets (25, 45) by VHL-KO versus WT D11 TIL. Genes with less than 1.5-fold change in expression were excluded. (D) GSEA of Trm signature in VHL-KO versus WT D11 TILs. (F) Comparison of T cell exhaustion signatures for Trm, TE, LLEC, and Tem between VHL-KO and WT D11 TILs (top) and small intestine intraepithelial P14 Trm relative to spleen P14 Tcm (45) (bottom). Genes with less than 1.5-fold change in expression were excluded. (G) GSEA of T cell exhaustion signature in VHL-KO versus WT D11 TILs and P14 Trm versus P14 Tcm. (H) Representative flow cytometric analysis (left) and quantification (right) of CD8+CD44+ VHL-KO and WT P14 TILs for T-bet, Eomes, Tcf-1, and granzyme-B. Data are representative of 3 independent experiments (n = 3 for Eomes and T-bet coexpression; n = 6 for Tcf-1). (I) Representative histograms of Eomes and Tcf-1 expression (left) and MFIs (right) in cotransferred donor P14 TIL populations. Overexpressed gene counts are shown at bottom of volcano plots, and statistical P values denote comparisons between indicated groups. Error bars represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (Student’s t test in H and I). FC, fold change; NS, not significant; NES, normalized enrichment score; FDR q value, FDR corrected P value.