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Hypoxia-inducible factor activity promotes antitumor effector function and tissue residency by CD8+ T cells
Ilkka Liikanen, … , Deborah A. Witherden, Ananda W. Goldrath
Ilkka Liikanen, … , Deborah A. Witherden, Ananda W. Goldrath
Published April 1, 2021
Citation Information: J Clin Invest. 2021;131(7):e143729. https://doi.org/10.1172/JCI143729.
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Research Article Immunology Article has an altmetric score of 7

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

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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 6

Immunotherapy with anti–PD-1 improves response to established tumors.

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Immunotherapy with anti–PD-1 improves response to established tumors.
(A...
(A) Tumor growth and survival in B16.gp33-bearing mice after transfer of WT or VHL-KO P14 cells and anti–PD-1(αPD-1) or PBS treatment. Tumor growth was compared by Mann-Whitney U test (middle) and survival was assessed by Bonferroni-corrected log-rank test (right). n = 12 (αPD-1) and n = 8 (isotype) in P14 transferred mice; n = 5 (αPD-1) and n = 3 (isotype) with no transfer. (B) Representative flow cytometry (left) and quantification of frequency (top right) and weight-adjusted numbers (bottom right) of CD69+CD103+ P14 TILs recovered at endpoint in A from mice treated with anti–PD-1 or PBS. n = 8 for WT donor with αPD-1; n = 5 for rest. (C) Specific target cell lysis of sorted donor WT and VHL-KO TILs after treatment with anti–PD-1 or isotype control antibody (bottom left). Ratio of cotransferred donor VHL-KO/WT TILs recovered (top right) and MFI of granzyme-B expression on sorted populations (bottom right) are shown. n = 4 for CTL assay; n = 7 for donor cell ratio; n = 4 for αPD-1; n = 3 for isotype control in granzyme-B panel. (D) Representative flow cytometry of IFN-γ and TNF-α coproduction by donor TIL populations upon restimulation, quantitated by frequency (top right) and compared by ratio of anti–PD-1 to control treatment (bottom right), n = 3 (top right), and n = 4 pooled (bottom right). Data are representative of 2 (A–C) and 4 (D) independent experiments. Error bars represent mean ± SEM. NS, not significant, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (Student’s t test C top and D bottom panel, 1-way ANOVA with Bonferroni correction for multiple comparisons in others, except as specified in A).

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