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. 2023 Nov 3:31:100744.
doi: 10.1016/j.omto.2023.100744. eCollection 2023 Dec 19.

Treatment with the PPARα agonist fenofibrate improves the efficacy of CD8+ T cell therapy for melanoma

Mohadeseh Hasanpourghadi  1 , Arezki Chekaoui  1 , Sophia Kurian  1 , Raj Kurupati  1   2 , Robert Ambrose  1 , Wynetta Giles-Davis  1 , Amara Saha  1 , Xu Xiaowei  3 , Hildegund C J Ertl  1
Affiliations

Treatment with the PPARα agonist fenofibrate improves the efficacy of CD8+ T cell therapy for melanoma

Mohadeseh Hasanpourghadi et al. Mol Ther Oncolytics. .

Abstract

Adoptive transfer of tumor antigen-specific CD8+ T cells can limit tumor progression but is hampered by the T cells' rapid functional impairment within the tumor microenvironment (TME). This is in part caused by metabolic stress due to lack of oxygen and glucose. Here, we report that fenofibrate treatment of human ex vivo expanded tumor-infiltrating lymphocytes (TILs) improves their ability to limit melanoma progression in a patient-derived xenograft (PDX) mouse model. TILs treated with fenofibrate, a peroxisome proliferator receptor alpha (PPARα) agonist, switch from glycolysis to fatty acid oxidation (FAO) and increase the ability to slow the progression of autologous melanomas in mice with freshly transplanted human tumor fragments or injected with tumor cell lines established from the patients' melanomas and ex vivo expanded TILs.

Keywords: PDX mouse model; PPARα agonist treatment; T cell metabolism; melanoma; tumor antigen-specific T cells.

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Conflict of interest statement

The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
Effect of FF on human melanoma growth in a PDX model (A) Experimental design. (B) Patient samples (Figure S1). (C) Progression of tumor fragments from patients D, E, and I in NSG mice treated with FF or DMSO. (D) Same data as in (C) but shown as linear regression curves of tumor diameter in centimeters over time for samples from individual patients. Data were normalized to a diameter of 1 on day 0 of drug treatment. Numbers show average slope of the linear regression curves. (E) Numbers of human T cells in various tissues after one to four passages. Zero passage reflects control mice that did not receive tumor fragments. Numbers were normalized to 105 live lymphoid cells. Data are shown as means ± SEM. (F) Gating scheme for human TILs: lymphocyte gate, single-cell gate, live-cell gate, CD4/CD8 gate.
Figure 2
Figure 2
Effect of FF on the ability of transferred CD8+ TILs to slow tumor progression (A) Experimental design. (B) Progression of tumors from the indicated patients in the four different treatment groups. (C) Same data as in (B) shown as linear regression curves. Data next to the graphs show the results of comparing the slope of the curves of individual mice by Fisher’s least significant difference (LSD) test. (D) Tumor progression shown as linear regression lines for tumor volume over time. (E) Kaplan-Meier survival graphs for the different groups receiving tumor cells from the indicated patients. Data were compared by Mantel-Cox test.
Figure 3
Figure 3
Effect of FF on TILs transferred into cell-line-derived tumor-bearing NSG mice (A) Recovery of lymphoid cells, human CD44+CD8+ T cells, and IFN-γ-producing human CD44+CD8+ T cells from spleens and tumors. Counts (lymphoid cells) or counts normalized to 105 live lymphoid cells are stacked for samples from different patients. (B) Lymphocyte and human CD8+ T cell counts by immunohistochemistry. Counts are normalized to a total area of 2 mm2. (C and D) Sections of tumors from NSG mice receiving patient M tumor cells. (C) TILs and mice treated with FA or FF. (D) TILs and mice treated with DMSO. (E) Percentages of human CD8+ T cells expressing the indicated markers. (F) Percentages of cell expressing combinations of markers determined by Boolean gating. (A, B, E, and F) Difference were calculated by two-way ANOVA with Tukey correction; data are shown as means ± SEM. (G) Differences in Cτ values between TILs and (H) tumor cells from individual sample of groups A and averaged samples from group B are shown in a heatmap for individual mice receiving samples from the indicated patients. p values comparing the original Cτ value. (F) Differences in Cτ values between tumor cells in isolated tumor samples of group C and averaged tumor samples from group D are shown in a heatmap for individual mice receiving samples from the indicated patients. p values comparing the original Cτ values for groups C and D. (E and F) Differences were calculated by multiple unpaired t test with two stage step-up method by Benjamini, Krieger, and Yekutieli.
Figure 4
Figure 4
Correlations Graph shows as heatmaps r values by Spearman correlation correlations on top with matching p values below.
See this image and copyright information in PMC

References

    1. Pham J.P., Joshua A.M., Da Silva I.P., Dummer R., Goldinger S.M. Chemotherapy in cutaneous melanoma: Is there still a role? Curr. Oncol. Rep. 2023;25:609–621. - PMC - PubMed
    1. Larkin J., Ascierto P.A., Dréno B., Atkinson V., Liszkay G., Maio M., Mandalà M., Demidov L., Stroyakovskiy D., Thomas L., et al. Combined Vemurafenib and Cobimetinib in BRAF- mutated melanoma. N. Engl. J. Med. 2014;371:1867–1876. - PubMed
    1. Long G.V., Flaherty K.T., Stroyakovskiy D., Gogas H., Levchenko E., De Braud F., Larkin J., Garbe C., Jouary T., Hauschild A., et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann. Oncol. 2017;28:1631–1639. - PMC - PubMed
    1. Wahid M., Jawed A., Mandal R.K., Dar S.A., Akhter N., Somvanshi P., Khan F., Lohani M., Areeshi M.Y., Haque S. Recent developments and obstacles in the treatment of melanoma with BRAF and MEK inhibitors. Crit. Rev. Oncol. Hematol. 2018;125:84–88. - PubMed
    1. Robert C., Thomas L., Bondarenko I., O’Day S., Weber J., Garbe C., Lebbe C., Baurain J.-F., Testori A., Grob J.-J., et al. Ipilimumab plus Dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 2011;364:2517–2526. - PubMed