Differential immunomodulatory activity of tumor cell death induced by cancer therapeutic toll-like receptor ligands

In this study we investigated immunological events associated with the induction of tumor cell death by poly(I:C) and imiquimod. A human head and neck squamous cell carcinoma (HNSCC) cell line was exposed to poly(I:C) and imiquimod, which were delivered exogenously via culture medium or via electroporation. Cell death and cell biological consequences thereof were analyzed. For in vivo analyses, a human xenograft and a syngeneic immunocompetent mouse model were used. Poly(I:C) induced cell death only if delivered by electroporation into the cytosol. Cell death induced by poly(I:C) resulted in cytokine release and activation of monocytes in vitro. Monocytes activated by the supernatant of cancer cells previously exposed to poly(I:C) recruited significantly more Th1 cells than monocytes exposed to control supernatants. If delivered exogenously, imiquimod also induced tumor cell death and some release of interleukin-6, but cell death was not associated with release of Th1 cytokines, interferons, monocyte activation and Th1 recruitment. Interestingly, intratumoral injection of poly(I:C) triggered tumor cell death in tumor-bearing mice and reduced tumor growth independent of TLR signaling on host cells. Imiquimod did not affect tumor size. Our data suggest that common cancer therapeutic RNA compounds can induce functionally diverse types of cell death in tumor cells with implications for the use of TLR ligands in cancer immunotherapy.
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research

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ConclusionsThe incidence of TE (neutralizing positive) ADAs against pembrolizumab was low in patients with advanced tumors. Furthermore, immunogenicity did not appear to have any clinically relevant effects on the exposure, safety, or efficacy of pembrolizumab.Trial registrationClinicalTrials.gov,NCT01295827 (February 15, 2011),NCT01704287 (October 11, 2012),NCT01866319 (May 31, 2013),NCT01905657 (July 23, 2013),NCT02142738 (May 20, 2014),NCT01848834 (May 8, 2013),NCT02255097 (October 2, 2014),NCT02460198 (June 2, 2015),NCT01953692 (October 1, 2013),NCT02453594 (May 25, 2015),NCT02256436 (October 3, 2014),NCT02335424 (Janu...
Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research
CONCLUSION: We introduced the first humanized in vitro microfluidic chip assay to test immunotherapeutic drugs against HNSCC patient samples. This assay could be used to predict the efficacy of immunotherapeutic drugs for individual patients. PMID: 31356815 [PubMed - as supplied by publisher]
Source: Experimental Cell Research - Category: Cytology Authors: Tags: Exp Cell Res Source Type: research
AbstractHead and neck cancers, including those of the lip and oral cavity, nasal cavity, paranasal sinuses, oropharynx, larynx and nasopharynx represent nearly 700,000 new cases and 380,000 deaths worldwide per annum, and account for over 10,000 annual deaths in the United States alone. Improvement in outcomes are needed for patients with recurrent and or metastatic squamous cell carcinoma of the head and neck (HNSCC). In 2016, the US Food and Drug Administration (FDA) granted the first immunotherapeutic approvals – the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab – for the treatment of pa...
Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research
Authors: Wang J, Linxweiler M, Yang W, Chan TA, Morris LGT Abstract The mutagenic effects of tobacco smoking increase the risk of the development of cancers of the lung, head and neck, and other anatomic sites. In a comparison of squamous cell carcinomas of the lung and the head and neck, we find that the immunomodulatory effects of smoking differ based on anatomic site. In both sites, the mutational signature of smoking is strongly associated with somatic mutational load. In head and neck squamous cell carcinoma, the mutational signature of tobacco exposure is associated with a strongly immunosuppressive tumor mic...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
Head and neck squamous cell carcinoma (HNSCC) originates from squamous epithelium of the upper aerodigestive tract and is the most common malignancy in the head and neck region. Among HNSCCs, oropharynx squamo...
Source: Journal of Translational Medicine - Category: Research Authors: Tags: Research Source Type: research
Abstract Recent reports describe how genome-wide transcriptional analysis of cancer tissues can be exploited to identify molecular signatures of immune infiltration in cancer. We hypothesize that immune infiltration in cancer may also be defined by changes in certain epigenetic signatures. In this context, a primary objective is to identify site-specific CpG markers whose levels of methylation may be highly indicative of known transcriptional markers of immune infiltration such as GZMA, PRF1, T cell receptor genes, PDCD1, and CTLA4. This has been accomplished by integrating genome-wide transcriptional expression a...
Source: Advances in Cancer Research - Category: Cancer & Oncology Authors: Tags: Adv Cancer Res Source Type: research
Head and neck squamous cell carcinoma (HNSCC) can be cured with surgery and radiotherapy with or without systemic therapy, but locoregional recurrence is not uncommon. Cancers that recur locally are often considered inoperable, and may pose a therapeutic challenge, because reirradiation is often associated with substantial toxicity, and chemotherapy and immunotherapy have limited efficacy in most patients [1,2]. Intensity modulated radiotherapy (IMRT) and stereotactic radiotherapy (SRT) may allow delivery of relatively high re-treatment radiation doses without excessive adverse effects to the normal tissues and may improve...
Source: Radiotherapy and Oncology - Category: Radiology Authors: Tags: Original Article Source Type: research
Discussion MDSCs violently emerge in pathological conditions in an attempt to limit potentially harmful immune and inflammatory responses. Mechanisms supporting their expansion and survival are deeply investigated in cancer, in the perspective to reactivate specific antitumor responses and prevent their contribution to disease evolution. These findings will likely contribute to improve the targeting of MDSCs in anticancer immunotherapies, either alone or in combination with immune checkpoint inhibitors. New evidence indicates that the expansion of myeloid cell differentiation in pathology is subject to fine-tuning, as its...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Conclusion MTDH is pro-oncogenic factor playing multifaceted and diverse roles in cancer progression. Its association and central role in regulating signaling pathways such a MAPK, wnt/β-catenin, PI3K/AkT, NF-κβ pathways in various cancers shows that it plays a vital role in metastasis. MTDH contribution to chemo and radiotherapy resistance provides a new direction for the development of anticancer therapeutics. Multiple mechanisms converge to promote expression of MTDH in cancers. Further studies are therefore warranted to determine whether the elevated MTDH expression has prognostic value for development...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Reena Goswami1, Gayatri Subramanian2, Liliya Silayeva1, Isabelle Newkirk1, Deborah Doctor1, Karan Chawla2, Saurabh Chattopadhyay2, Dhyan Chandra3, Nageswararao Chilukuri1 and Venkaiah Betapudi1,4* 1Neuroscience Branch, Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen, MD, United States 2Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States 3Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States 4Department of Physiology and Biophysics, Case Western Reserve University, Clev...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
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