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 1

HIF-dependent accumulation of TILs and control of tumor growth by VHL-deficient CD8+ T cells.

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HIF-dependent accumulation of TILs and control of tumor growth by VHL-de...
(A–B) Tumor growth and survival of (A) B16.gp33- or (B) MC38.gp33-bearing C57BL/6J mice after transfer of Vhlfl/fl dLck-Cre– (WT) or Vhlfl/fl dLck-Cre+ (VHL-KO) P14 cells, n = 7 in A and 9 in B (experimental) and 5 in A and 6 in B (control). (C) Images (middle) and quantification (right) of metastatic lung tumors in polyclonal WT and VHL-KO mice after i.v. challenge with B16.gp33 cells. (D) Immunofluorescence microscopy of CD8α (red) and DAPI (blue) in representative tumor lesions from C at 20× magnification; tumor regions indicated by dotted lines (left) and quantification of CD8+ TILs per tumor area unit (AU; right). Data are combined from 2 independent experiments with 6 × 105 B16.gp33 cells injected into 11 WT and 10 VHL-KO mice. Corresponding results were obtained in 2 additional experiments with 4.5 × 105 tumor cells, n = 9 mice per group. (E) Number of donor P14 cells from tumor (TILs) and spleen from mice bearing B16.gp33 (left) and MC38.gp33 (right) tumors at endpoint of efficacy experiments (A and B), n = 9 for WT and 10 for VHL-KO for B16.gp33, n = 3 per group for MC38.gp33. (F) Frequency of donor P14 cells recovered from KMR.gp33 tumors or spleen 7 days after cotransfer of WT and VHL-KO cells, n = 4. (G) Tumor growth and survival of B16.gp33 tumor–bearing mice after transfer of WT, VHL-KO, or Vhlfl/fl-Hif1afl/fl-Epas1fl/fl dLck-Cre+ (VHL-HIF-1α-HIF-2α-KO) P14 cells, n = 5 per group. Data are representative of 3 independent experiments except as stated in D. Bars and error represent mean ± SEM. NS, not significant, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 2-tailed Student’s t test or Mann-Whitney U test (tumor growth) and Bonferroni-corrected log-rank test (survival), (*) failed to reach the Bonferroni-corrected threshold although showing P < 0.05.