CD137 Enhancement of HPV Positive Head and Neck Squamous Cell Carcinoma Tumor Clearance (original) (raw)
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International Journal of Cancer, 2013
The increasing incidence of human papillomavirus (HPV) related oropharyngeal squamous cell carcinoma (OSSC) demands development of novel therapies. Despite presenting at a more advanced stage, HPV(1) oropharyngeal squamous cell carcinoma (OSCC) have a better prognosis than their HPV(2) counterparts. We have previously demonstrated that clearance of HPV(1) OSCC during treatment with radiation and chemotherapy requires an immune response which is likely responsible for the improved clinical outcomes. To further elucidate the mechanism of immune-mediated clearance, we asked whether radiation therapy induces tumor cell changes that allow the body to recognize and aid in tumor clearance. Here, we describe a radiation-induced change in tumor surface protein expression that is critical for immune-mediated clearance. Radiation therapy decreases surface expression of CD47, a self-marker. CD47 is frequently overexpressed in head and neck squamous cell carcinoma and radiation induces a decrease of CD47 in a dose-dependent manner. We show that both in vitro and in vivo tumor cell CD47 protein levels are restored over time after sublethal radiation exposure and that protein levels on adjacent, normal tissues remain unaffected. Furthermore, reduction of tumor cell CD47 increases phagocytosis of these cells by dendritic cells and leads to increased interferon gamma and granzyme production from mixed lymphocytes. Finally, decreasing tumor cell CD47 in combination with standard radiation and chemotherapy results in improved immune-mediated tumor clearance in vivo. These findings help define an important mechanism of radiation-related immune clearance and suggest that decreasing CD47 specifically on tumor cells may be a good therapeutic target for HPV related disease.
Cancer Research, 2005
Human papillomavirus (HPV)-associated squamous cell carcinoma of the head and neck (SCCHN) seems to be a suitable target for cancer vaccination. HPV-encoded oncogenic proteins, such as E7, are promising tumor-specific antigens and are obligatory for tumor growth. Because few immunologic studies have analyzed the endogenous HPV-specific immune response in this subset of SCCHN patients, we studied T-cell frequencies against HPV-16 E7 11-20 or E7 86-93 in tumorbearing, human leukocyte antigen (HLA)-A*0201 + SCCHN patients, whose tumors were either HPV-16 + or HPV-16 À . In HPV-16 + SCCHN patients, frequencies of T cells against either peptide were significantly elevated (P < 0.005) compared with HPV-16 À patients or healthy volunteers. Tetramer + T cells showed evidence of terminally differentiated phenotype (CD45RA + CCR7 À ) and an elevated level of CD107a staining for degranulation. Despite detectable expression of the restricting HLA class I allele, HLA-A*0201-E7 11-20 -or HLA-A*0201-E7 86-93 -specific CTL obtained by in vitro stimulation of healthy donor peripheral blood mononuclear cells only recognize a naturally HPV-16-transformed, HLA-A*0201 + SCCHN cell line after pretreatment with IFN-;. This cell line had little or no expression of LMP2, TAP1, and tapasin, critical components of the HLA class I antigen-processing machinery, which were up-regulated by IFN-; treatment. Immunohistochemistry of HPV-16 + SCCHN tumors showed that these antigen-processing machinery components are downregulated in tumors in vivo compared with adjacent normal squamous epithelium. Thus, immunity to HPV-16 E7 is associated with the presence of HPV-16 infection and presentation of E7-derived peptides on SCCHN cells, which show evidence of immune escape. These findings support further development of E7-specific immunotherapy and strategies for up-regulation of antigen-processing machinery components in HPV-associated SCCHN. (Cancer Res 2005; 65(23): 11146-55)
Cancer research, 2018
Human papillomavirus subtype 16 (HPV16) is the primary cause of an increasing number of head and neck squamous cell carcinomas (HNSCCs), providing strong rationale for T-cell immune therapies against HPV+ HNSCC. Here we assess immunogenicity of HPV16-specific CD8+ T-cells (CTL) and characterize HPV-specific mechanisms of T-cell dysfunction. We identified 16 strong and 29 moderately immunogenic CTL-epitopes from HPV16 E2, E6 and E7 antigens restricted by 12 common HLA class I alleles. E2-specific CTL-reactivity was higher in HPV+ HNSCC patients than in healthy controls (>3-fold, P = 0.026). Patient-derived E2, E6, and E7 peripheral CTLs exhibited heterogeneity in dysfunction phenotypes. Immunogenomic analyses of 119 HNSCC transcriptomes revealed high T-cell infiltration and dysfunction in HPV+ HNSCC as well as correlation of HPV antigen expression with T-cell exhaustion gene signatures. Indoleamine 2,3-dioxygenase (IDO-1) was strongly expressed in HPV+ HNSCC versus HPV- HNSCC (P =...
TIGIT as a therapeutic target of HPV-positive head and neck squamous cell carcinomas
2021
The tumor immune microenvironment (TIME) of treatment-naïve, human papillomavirus-positive head and neck squamous cell carcinoma (HPV-positive HNSCC) was interrogated at single-cell level to identify influential immune checkpoints as therapeutic targets. Single-cell transcriptome profiling revealed enrichment of numerous cell-cell interactions mediated by TIGIT-PVR/NECTIN2 in the TIME of HPV-positive HNSCC versus normal tonsil. TIGIT was the most differentially upregulated immune checkpoint on clonally expanded CD8+ T cells and was abundant on antigen-experienced, tissue-resident memory CD8+ T cell and T-regulatory subsets. TIGIT ligands PVR/NECTIN1/2 were abundant on mature regulatory dendritic cells, immunosuppressive plasmacytoid DCs, and macrophages. TIGIT and PD-1 co-blockade in the mEER murine model of HPV-positive HNSCC significantly reduced tumor growth, improved survival, restored effector function of HPV16 E7-specific CD8+ T cells, natural killer cells, and DCs, and confer...
CD137 Accurately Identifies and Enriches for Naturally Occurring Tumor-Reactive T Cells in Tumor
Clinical Cancer Research, 2014
Purpose: Upregulation of CD137 (4-1BB) on recently activated CD8 þ T cells has been used to identify rare viral or tumor antigen-specific T cells from peripheral blood. Here, we evaluated the immunobiology of CD137 in human cancer and the utility of a CD137-positive separation methodology for the identification and enrichment of fresh tumor-reactive tumor-infiltrating lymphocytes (TIL) or tumor-associated lymphocytes (TAL) from ascites for use in adoptive immunotherapy.
International Journal of Cancer, 2013
Patients with human papillomavirus (HPV)-related oropharyngeal tumors display improved prognosis. The biological basis of this tumor phenotype is poorly understood. We investigated whether increased lymphocyte infiltrate in HPV-positive oropharyngeal squamous cell carcinomas could account for better prognosis. We previously identified, in an Affymetrix GeneChip analysis of 83 HPV-unrelated and 11 HPV-related squamous cell carcinoma of the oropharynx, several candidate genes, including CD8α and CD3ζ. Their expression was validated in this study by qRT-PCR on an independent clinical series of 144 oropharyngeal tumors. Immunohistochemical staining of tumor specimens was performed to evaluate infiltration of tumor stroma by CD8+ and CD4+ lymphocytes. The prognostic value of CD8α and CD3ζ expression levels was measured by Kaplan-Meier and Cox regression model analyses. Immune response-related signaling pathways were found to be deregulated in HPV-positive oropharyngeal tumors. Expression of CD8α, CD3ζ, granzyme K, CD28 and integrin αL RNAs was upregulated in HPV-positive lesions when compared with HPV-unrelated tumors (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Stroma of HPV-positive tumors was frequently and strongly infiltrated by CD8α- and CD3ζ-positive T cells. CD8α RNA expression correlated with both improved global (Kaplan-Meier; p = 0.005; Cox regression: p = 0.003) and disease-free (Cox regression: p = 0.04) survival. CD3ζ RNA expression correlated with improved overall survival (Cox regression: p = 0.024). These results suggest that an increased cytotoxic T-cell-based antitumor immune response is involved in improved prognosis of patients with HPV-positive tumors.
Boosting Cancer Immunotherapy with Anti-CD137 Antibody Therapy
Clinical Cancer Research, 2015
In the last five years, immunomodulatory antibodies have revolutionized cancer immunotherapy. CD137, a member of the tumor necrosis factor receptor superfamily, represents a promising target for enhancing anti-tumor immune responses. CD137 helps regulate the activation of many immune cells, including CD4 + T cells, CD8 + T cells, dendritic cells and natural killer cells. Recent studies indicate that the anti-tumor efficacy of therapeutic tumor-targeting antibodies can be augmented by the addition of agonistic antibodies targeting CD137. As ligation of CD137 provides a co-stimulatory signal in multiple immune cell subsets, combination therapy of CD137 antibody with therapeutic antibodies and/or vaccination has the potential to improve cancer treatment.
In vivo depletion of DC impairs the anti-tumor effect of agonistic anti-CD137 mAb
European Journal of Immunology, 2009
Anti-CD137 mAb are capable of inducing tumor rejection in several syngeneic murine tumor models and are undergoing clinical trials for cancer. The anti-tumor effect involves co-stimulation of tumor-specific CD8+ T cells. Whether antigen cross-presenting DC are required for the efficacy of anti-CD137 mAb treatment has never been examined. Here we show that the administration of anti-CD137 mAb eradicates EG7-OVA tumors by a strictly CD8β+ T-cell-dependent mechanism that correlates with increased CTL activity. Ex vivo analyses to determine the identity of the draining lymph node cell type responsible for tumor antigen cross-presentation revealed that CD11c+ cells, most likely DC, are the main players in this tumor model. A minute number of tumor cells, revealed by the presence of OVA cDNA, reach tumor-draining lymph nodes. Direct antigen presentation by tumor cells themselves also participates in anti-OVA CTL induction. Using CD11c diphtheria toxin receptor-green fluorescent proteinC57BL/6 BM chimeric mice, which allow for sustained ablation of DC with diphtheria toxin, we confirmed the involvement of DC in tumor antigen cross-presentation in CTL induction against OVA257–264 epitope and in the antitumor efficacy induced by anti-CD137 mAb.