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TOX and TOX2 Transcription Factors Cooperate with NR4A Transcription Factors to Impose CD8+ T Cell Exhaustion

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TOX and TOX2 Transcription Factors Cooperate with NR4A Transcription Factors to Impose CD8+ T Cell Exhaustion Correction IMMUNOLOGY AND INFLAMMATION Correction for “TOX and TOX2 transcription factors cooper- Wu, Li-Fan Lu, Patrick G. Hogan, Avinash Bhandoola, and + ate with NR4A transcription factors to impose CD8 T Anjana Rao, which was first published May 31, 2019; cell exhaustion,” by Hyungseok Seo, Joyce Chen, Edahí 10.1073/pnas.1905675116 (Proc. Natl. Acad. Sci. U.S.A. 116, González-Avalos, Daniela Samaniego-Castruita, Arundhoti 12410–12415). Das, Yueqiang H. Wang, Isaac F. López-Moyado, Romain The authors note that Fig. 1 appeared incorrectly. The cor- O. Georges, Wade Zhang, Atsushi Onodera, Cheng-Jang rected figure and its legend appear below. A B B16-hCD19 TumorCAR T cellCAR TIL Analysis D24 D24 inoculation Adoptive Transfer D20 D20 D0 D12 D16 D20 D24 D16 D16 C57BL/6 D12 D12 TOX Relative cell number TOX: PE PD-1: APC PD-1 CD CORRECTION in vitro CAR T 20 100 in vitro CAR T ** CAR TIL ** 15 80 CAR TIL 60 ** 10 ** ** 40 (v.s. hprt) (v.s. 5 20 Relative expression 0 TNF: BV421 0 Tox Tox2 IFN-APC cells T Cytokine+ CAR TNF IFN E 60 **** In vitro CAR T TNF+IFN- CAR TIL p<0.0001 30 Specific lysis (%) 0 10:1 3:1 1:1 Effector:Target ratio Fig. 1. TOX transcription factors are highly expressed in exhausted CAR TILs in solid tumors. (A) Experimental scheme for analyzing tumor-infiltrating CAR T cells (CAR TILs); 5 × 105 B16-hCD19 tumor cells were inoculated subcutaneously into C57BL/6 mice. Twelve days later, 1.5 × 106 CAR T cells were adoptively transferred into the tumor-bearing mice by intravenous injection. CAR TILs were isolated every 4 d after CAR T cell transfer. (B–E) Gray color (dots, histograms, and shading) indicates T cells retrovirally transduced with the CAR and analyzed in vitro, and the orange, green, and blue colors indicate CAR TILs analyzed the indicated number of days after CAR T cell transfer. (B, Left and Center) Expression of TOX and PD-1 was analyzed by flow cytometry (PE: phycoerythrin, APC: allophycocyanin). Shown are histograms for TOX and PD-1 expression of CAR TILs on days 12, 16, 20, and 24 after tumor inoculation; “in vitro CAR T” refers to CAR T cells before adoptive transfer. (B, Right) Combined flow cytometry plot showing PD-1 and TOX expression on in vitro-transduced CAR T cells (gray) as well as CAR TILs isolated on day 24 (blue). (C) mRNA expression levels of Tox and Tox2 (relative to Hprt) in bulk CAR TILs on day 24. (D, Left) Representative flow cytometry plot showing TNF and IFN-γ expression after EL4-hCD19 cells restimulation in in vitro-transduced CAR T cells (gray) and CAR TILs isolated on day 24 (blue). (D, Right) Quantification of cytokine production (three mice per group). The data from C and D were analyzed by Student’s t test. **P ≤ 0.01. (E) In vitro-transduced CAR T cells and CAR TILs were cocultured with tumor cells expressing MC38-hCD19, and target cell lysis was measured 5 h later. The data are representative of two biologically independent experiments. The data from the two groups in E were analyzed by two-way ANOVA with a Bonferroni multiple comparisons test. ****P ≤ 0.0001. Published under the PNAS license. First published September 16, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1914896116 www.pnas.org PNAS | September 24, 2019 | vol. 116 | no. 39 | 19761 Downloaded by guest on September 29, 2021 TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion Hyungseok Seoa, Joyce Chena,b,c,d, Edahí González-Avalosa,e, Daniela Samaniego-Castruitaa,f, Arundhoti Dasg, Yueqiang H. Wangg, Isaac F. López-Moyadoa,d,e, Romain O. Georgesa, Wade Zhanga,h, Atsushi Onoderaa,i,j, Cheng-Jang Wuk, Li-Fan Luk,l,m, Patrick G. Hogana,l,m, Avinash Bhandoolag, and Anjana Raoa,c,d,l,m,1 aDivision of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037; bBiomedical Sciences Graduate Program, School of Medicine, University of California, San Diego, La Jolla, CA 92093; cDepartment of Pharmacology, University of California, San Diego, La Jolla, CA 92093; dSanford Consortium for Regenerative Medicine, La Jolla, CA 92037; eBioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093; fBiological Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093; gNational Cancer Institute, National Institutes of Health, Bethesda, MD 20184; hBioengineering Graduate Program, Bioengineering Department, University of California, San Diego, La Jolla, CA 92093; iDepartment of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; jInstitute for Global Prominent Research, Chiba University, Chiba 263-8522, Japan; kDivision of Biological Sciences, Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093; lProgram in Immunology, University of California, San Diego, La Jolla, CA 92037; and mMoores Cancer Center, University of California, San Diego, La Jolla, CA 92093 Contributed by Anjana Rao, May 1, 2019 (sent for review April 3, 2019; reviewed by Jeremy Boss and Linda M. Bradley) T cells expressing chimeric antigen receptors (CAR T cells) have including PD-1, CTLA-4, T cell immunoglobin and mucin-domain shown impressive therapeutic efficacy against leukemias and containing-3 (TIM3), lymphocyte activation gene 3 (LAG3), and lymphomas. However, they have not been as effective against T cell immunoreceptor with immunoglobulin and ITIM domains solid tumors because they become hyporesponsive (“exhausted” (TIGIT). Anti–PD-1/PD-L1 therapy not only “rejuvenates” the + or “dysfunctional”) within the tumor microenvironment, with de- exhausted CD8 T cells themselves but also, allows expansion of a + creased cytokine production and increased expression of several more “stem-like” CD8 T cell population that expresses the inhibitory surface receptors. Here we define a transcriptional net- – + transcription factor T cell factor 1 (TCF1) (7 9). However, only a INFLAMMATION work that mediates CD8 T cell exhaustion. We show that the subset of patients achieves complete remission with checkpoint IMMUNOLOGY AND high-mobility group (HMG)-box transcription factors TOX and blockade therapies, a problem that can potentially be countered by TOX2, as well as members of the NR4A family of nuclear receptors, using combinations of antibodies to multiple inhibitory receptors are targets of the calcium/calcineurin-regulated transcription fac- (1, 2). Likewise, CAR T cell therapy has been remarkably effective tor NFAT, even in the absence of its partner AP-1 (FOS-JUN). Using against hematopoietic cancers, such as B cell chronic lymphocytic a previously established CAR T cell model, we show that TOX and + + leukemia, but it has not been very effective against solid tumors, TOX2 are highly induced in CD8 CAR PD-1high TIM3high (“exhausted”) tumor-infiltrating lymphocytes (CAR TILs), and CAR TILs deficient in both TOX and TOX2 (Tox DKO) are more effective than wild-type Significance (WT), TOX-deficient, or TOX2-deficient CAR TILs in suppressing tu- mor growth and prolonging survival of tumor-bearing mice. Like A recent exciting development in cancer therapy involves using a NR4A-deficient CAR TILs, Tox DKO CAR TILs show increased cytokine patient’s own immune system to attack cancers. The attack is + expression, decreased expression of inhibitory receptors, and in- carried out by CD8 T cells that destroy the malignant cells; after creased accessibility of regions enriched for motifs that bind activa- infiltrating tumors, however, these cells become hyporesponsive tion-associated nuclear factor κB(NFκB) and basic region-leucine (“exhausted”) and exhibit diminished ability to control the tu- zipper (bZIP) transcription factors. These data indicate that Tox mors. In this study, we describe the transcriptional network that + and Nr4a transcription factors are critical for the transcriptional pro- mediates CD8 T cell exhaustion. We show that an initiating gram of CD8+ T cell exhaustion downstream of NFAT. We provide NFAT induces secondary transcription factors of the TOX and + evidence for positive regulation of NR4A by TOX and of TOX by NR4A families, which are critical for CD8 T cell exhaustion NR4A, and suggest that disruption of TOX and NR4A expression or downstream of NFAT. We identify positive feedback loops con- activity could be promising strategies for cancer immunotherapy. nectingTOXandNR4Aandsuggestthat diminished expression or activity of these transcription factors may be useful to improve + TOX | TOX2 | NR4A | NFAT | CD8 T cell hyporesponsiveness effector function in cancer immunotherapy. Author contributions: H.S., J.C., and A.R. designed research; H.S., R.O.G., W.Z., and A.O. he goal of cancer immunotherapy is to harness the immune performed research; A.D., Y.H.W., C.-J.W., L.-F.L., and A.B. contributed new reagents/ − − Tsystem to destroy tumors in cancer patients. Two approaches analytic tools; A.B. provided the Tox2 / mice; H.S., E.G.-A., D.S.-C., I.F.L.-M., P.G.H., have achieved remarkable success: “immune checkpoint blockade” and A.R. analyzed data; and H.S., J.C., P.G.H., and A.R. wrote the paper. therapies involving treatment of cancer patients with blocking an- Reviewers: J.B., Emory University School of Medicine; and L.M.B., Sanford Burnham Prebys tibodies to inhibitory cell surface receptors, including the cytotoxic Medical Discovery Institute. T lymphocyte-associated protein 4 (CTLA-4), programmed cell Conflict of interest statement: The La Jolla Institute of Immunology has a pending patent, PCT/US2018/062354, covering the use and production of engineered immune cells to death protein 1 (PD-1), and the programmed cell death protein 1 disrupt NFAT-AP1 pathway transcription factors, including TOX and NR4A family mem- ligand (PD-L1) (1, 2); and the use of T cells expressing chimeric bers, with H.S., J.C., and A.R.
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