Publications by Year: 2018

Sheng W, LaFleur MW, Nguyen TH, Chen S, Chakravarthy A, Freeman GJ, Carvalho DD, He HH, Sharpe AH, Shi Y. LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade. Cell. 2018;174 (3) :549-563.Abstract

Chromatin regulators play a broad role in regulating gene expression and, when gone awry, can lead to cancer. Here, we demonstrate that ablation of the histone demethylase LSD1 in cancer cells increases repetitive element expression, including endogenous retroviral elements (ERVs), and decreases expression of RNA-induced silencing complex (RISC) components. Significantly, this leads to double-stranded RNA (dsRNA) stress and activation of type 1 interferon, which stimulates anti-tumor T cell immunity and restrains tumor growth. Furthermore, LSD1 depletion enhances tumor immunogenicity and T cell infiltration in poorly immunogenic tumors and elicits significant responses of checkpoint blockade-refractory mouse melanoma to anti-PD-1 therapy. Consistently, TCGA data analysis shows an inverse correlation between LSD1 expression and CD8+ T cell infiltration in various human cancers. Our study identifies LSD1 as a potent inhibitor of anti-tumor immunity and responsiveness to immunotherapy and suggests LSD1 inhibition combined with PD-(L)1 blockade as a novel cancer treatment strategy.

PubMed DOI

Tan CL, Peluso MJ, Drivjers JM, Mera CM, Grande SM, Brown KE, Godec J, Freeman GJ, Sharpe AH. CD160 Stimulates CD8+ T Cell Responses and Is Required for Optimal Protective Immunity to Listeria monocytogenes. ImmunoHorizons. 2018;2 (7) :238-250.Abstract

CD160 promotes NK cell cytotoxicity and IFN-γ production, but the function of CD160 on CD8+T cells remains unclear with some studies supporting a coinhibitory role and others a costimulatory role. In this study, we demonstrate that CD160 has a costimulatory role in promoting CD8+ T cell effector functions needed for optimal clearance of oral Listeria monocytogenes infection. CD160−/− mice did not clear oral L. monocytogenes as efficiently as wild type (WT) littermates. WT RAG−/− and CD160−/− RAG−/− mice similarly cleared L. monocytogenes, indicating that CD160 on NK cells does not contribute to impaired L. monocytogenes clearance. Defective L. monocytogenes clearance is due to compromised intraepithelial lymphocytes and CD8+ T cell functions. There was a reduction in the frequencies of granzyme B–expressing intraepithelial lymphocytes in L. monocytogenes–infected CD160−/−mice as compared with WT littermate controls. Similarly, the frequencies of granzyme B–expressing splenic CD8+ T cells and IFN-γ and TNF-α double-producer CD8+ T cells were significantly reduced in L. monocytogenes–infected CD160−/− mice compared with WT littermates. Adoptive transfer studies showed that RAG−/− recipients receiving CD160−/− CD8+ T cells had a higher mortality, exhibited more weight loss, and had a higher bacterial burden compared with RAG−/− recipients receiving WT CD8+ T cells. These findings demonstrate that CD160 provides costimulatory signals to CD8+ T cells needed for optimal CD8+ T cell responses and protective immunity during an acute mucosal bacterial infection.

PubMed DOI

LaFleur MW, Muroyama Y, Drake CG, Sharpe AH. Inhibitors of the PD-1 Pathway in Tumor Therapy. J Immunol. 2018;200 (2) :375-383.Abstract

The programmed death 1 (PD-1) pathway delivers inhibitory signals that function as a brake for immune responses. This pathway limits the initiation and duration of immune responses, thereby protecting tissues from immune-mediated damage and autoimmune diseases. However, the PD-1 pathway also inhibits immune responses to tumors. The critical role of PD-1 in preventing antitumor immunity is demonstrated by the transformative effects of PD-1 pathway blockade in a broad range of cancers with the hallmark of durability of response. Despite this success, most patients do not respond to PD-1 monotherapy, and some patients experience adverse events. In this review, we discuss the functions of the PD-1 pathway and its translation to cancer immunotherapy. We also consider current challenges and opportunities for PD-1 cancer immunotherapy, including mechanisms of response and resistance, identification of biomarkers of response to PD-1 therapy, characterization and treatment of PD-1 therapy-related adverse events, and development of safe and effective combination therapies.

PubMed DOI