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Histone deacetylase inhibition promotes intratumoral CD8⁺ T-cell responses, sensitizing murine breast tumors to anti-PD1.

ABSTRACT: Histone deacetylase (HDAC) inhibitors impair tumor cell proliferation and alter gene expression. However, the impact of these changes on anti-tumor immunity is poorly understood. Here, we showed that the class I HDAC inhibitor, entinostat (ENT), promoted the expression of immune-modulatory molecules, including MHCII, costimulatory ligands, and chemokines on murine breast tumor cells in vitro and in vivo. ENT also impaired tumor growth in vivo-an effect that was dependent on both CD8⁺ T cells and IFN?. Moreover, ENT promoted intratumoral T-cell clonal expansion and enhanced their functional activity. Importantly, ENT sensitized normally unresponsive tumors to the effects of PD1 blockade, predominantly through increases in T-cell proliferation. Our findings suggest that class I HDAC inhibitors impair tumor growth by enhancing the proliferative and functional capacity of CD8⁺ T cells and by sensitizing tumor cells to T-cell recognition.

SUBMITTER: McCaw TR

PROVIDER: S-EPMC6879872 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Histone deacetylase inhibition promotes intratumoral CD8<sup>+</sup> T-cell responses, sensitizing murine breast tumors to anti-PD1.

McCaw Tyler R TR Li Mei M Starenki Dmytro D Liu Mingyong M Cooper Sara J SJ Arend Rebecca C RC Forero Andres A Buchsbaum Donald J DJ Randall Troy D TD

Cancer immunology, immunotherapy : CII 20191112 12

Histone deacetylase (HDAC) inhibitors impair tumor cell proliferation and alter gene expression. However, the impact of these changes on anti-tumor immunity is poorly understood. Here, we showed that the class I HDAC inhibitor, entinostat (ENT), promoted the expression of immune-modulatory molecules, including MHCII, costimulatory ligands, and chemokines on murine breast tumor cells in vitro and in vivo. ENT also impaired tumor growth in vivo-an effect that was dependent on both CD8<sup>+</sup> ...[more]

PMID: 31720815

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Project description:BackgroundThis study aimed to explore the potentially predictive role and dynamic changes of immune checkpoints on T cell subsets in patients with breast cancer receiving neoadjuvant chemotherapies.MethodsFluorescent multiplex immunohistochemistry (mIHC) was used to stain CD4, CD8, PD1, TIM3, and cytokeratins simultaneously in paired breast cancer samples before and after neoadjuvant therapies (NAT) in a prospective cohort (n = 50). Singleplex IHC was conducted to stain for CD3 in 100 cases with inclusion of extra retrospective 50 cases. Cell levels were correlated with clinicopathological parameters and pathological complete response (pCR).ResultsIn pretreatment tumors, the percentages of infiltrating CD8+ , PD1+ , PD1+ CD8+ , and the ratio of PD1+ CD8+ /CD8+ cells, were higher in pCR than non-pCR patients in either the stromal or intratumoral area, but PD1+ CD4+ , TIM3+ CD4+ , TIM3+ CD8+ cells and CD4+ /CD8+ ratio was not. Multivariate analyses showed that the percentage of intratumoral CD8+ cells (OR, 1.712; 95% CI: 1.052-2.786; P = 0.030) and stromal PD1+ CD8+ /CD8+ ratio (OR, 1.109; 95% CI: 1.009-1.218; P = 0.032) were significantly associated with pCR. Dynamically, reduction in the percentages of PD1+ , CD8+ and PD1+ CD8+ cells after therapy strongly correlated with pCR. Notably, incremental percentages of PD1+ CD8+ cells, rather than TIM3+ CD8+ , were shown in tumors from non-pCR patients after NAT. CD3 staining confirmed the percentage of T cells were associated with pCR.ConclusionsPD1+ CD8+ rather than TIM3+ CD8+ cells are main predictive components within tumor-infiltrating T cells in NAT breast cancer patients. Dynamically incremental levels of PD1+ CD8+ cells occurred in non-pCR cases after NAT, suggesting the combination of chemotherapy with PD1 inhibition might benefit these patients.Key pointsSIGNIFICANT FINDINGS OF THE STUDY: PD1+ CD8+ , rather than TIM3+ CD8+ , T cells are the main component to predict the response of neoadjuvant therapies in breast cancer.What this study addsIncremental levels of PD1+ CD8+ T cells in non-pCR post-NAT tumors suggest PD1 inhibition might benefit in the neoadjuvant setting.

Dataset Information

Histone deacetylase inhibition promotes intratumoral CD8+ T-cell responses, sensitizing murine breast tumors to anti-PD1.

Publications

Histone deacetylase inhibition promotes intratumoral CD8<sup>+</sup> T-cell responses, sensitizing murine breast tumors to anti-PD1.

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Histone deacetylase inhibition promotes intratumoral CD8⁺ T-cell responses, sensitizing murine breast tumors to anti-PD1.