HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity
Andrew Nguyen, Louisa Ho, Richard Hogg, Lan Chen, Scott R. Walsh, Yonghong Wan
Andrew Nguyen, Louisa Ho, Richard Hogg, Lan Chen, Scott R. Walsh, Yonghong Wan
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Research Article Immunology

HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity

Abstract

Adoptive cell therapy (ACT) with tumor-specific memory T cells has shown increasing efficacy in regressing solid tumors. However, tumor antigen heterogeneity represents a longitudinal challenge for durable clinical responses due to the therapeutic selective pressure for immune escape variants. Here, we demonstrated that delivery of the class I histone deacetylase inhibitor MS-275 promoted sustained tumor regression by synergizing with ACT in a coordinated manner to enhance cellular apoptosis. We found that MS-275 altered the tumor inflammatory landscape to support antitumor immunoactivation through the recruitment and maturation of cross-presenting CD103+ and CD8+ DCs and depletion of Tregs. Activated endogenous CD8+ T cell responses against nontarget tumor antigens were critically required for the prevention of tumor recurrence. Importantly, MS-275 altered the immunodominance hierarchy by directing epitope spreading toward the endogenous retroviral tumor–associated antigen p15E. Our data suggest that MS-275 in combination with ACT multimechanistically enhanced epitope spreading and promoted long-term clearance of solid tumors.

Authors

Andrew Nguyen, Louisa Ho, Richard Hogg, Lan Chen, Scott R. Walsh, Yonghong Wan

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Figure 4

Epitope spreading mobilizes tumor-rejecting, p15E-specific endogenous CD8+ T cell responses.

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Epitope spreading mobilizes tumor-rejecting, p15E-specific endogenous CD...
(A) In lymphocyte-deficient Rag2/Il2rg-DKO mice (n = 7–8 per group), 5-day-old intradermal B16-gp33 tumors were treated with ACT with or without MS-275. Tumor volumes were calculated on the basis of height, width, and length. Using C57BL/6 tumor-bearing mice treated with ACT+MS-275, (B) CD8+ T cells were positively enriched from digested tumors and cocultured with target cell lines at a 10:1 effector to target ratio. Killing was measured by MTT reduction and done in triplicate. (C and D) Five days after vaccination, the frequency of tumor antigen–specific CD8+ T cells in peripheral blood was determined by IFN-γ expression after ex vivo stimulation with peptides (n = 3 per group). (E and F) CFSEhi-labeled bulk splenocytes were pulsed with p15E peptide, mixed with CFSElo-labeled, unpulsed splenocytes at a 1:1 ratio, and infused into tumor-bearing mice 5 days after ACT+MS-275 treatment. P15E-specific killing was measured by the recovery of labeled, pulsed targets relative to unpulsed targets (n = 4 per group). Mice that were cured of B16-gp33 tumors during ACT+MS-275 were rechallenged with (G and H) natural, p15E-expressing MC38 tumors or (I and J) engineered, p15E-overexpressing MCA102 tumors and monitored for tumor growth and survival (n = 4 per group). Data are presented as the mean ± SEM. *P < 0.05 and **P < 0.01, by unpaired Student’s t test (B and F), 1-way ANOVA (C and D), or log-rank test (H and J).