Evasion of the host immune responses is critical for both persistent human papillomavirus (HPV) infection and associated cancer progression. We have previously shown that expression of the homeostatic chemokine CXCL14 is significantly downregulated by the HPV oncoprotein E7 during cancer progression. Restoration of CXCL14 expression in HPV-positive head and neck cancer (HNC) cells dramatically suppresses tumor growth and increases survival through an immunedependent mechanism in mice. Although CXCL14 recruits natural killer (NK) and T cells to the tumor microenvironment, the mechanism by which CXCL14 mediates tumor suppression through NK and/or T cells remained undefined. Here we report that CD8 + T cells are required for CXCL14-mediated tumor suppression. Using a CD8 + T-cell receptor transgenic model, we show that the CXCL14-mediated antitumor CD8 + T-cell responses require antigen specificity. Interestingly, CXCL14 expression restores major histocompatibility complex class I (MHC-I) expression on HPV-positive HNC cells downregulated by HPV, and knockdown of MHC-I expression in HNC cells results in loss of tumor suppression even with CXCL14 expression. These results suggest that CXCL14 enacts antitumor immunity through restoration of MHC-I expression on tumor cells and promoting antigen-specific CD8 + T-cell responses to suppress HPV-positive HNC.
Chemotherapeutic agents, e.g., cytarabine and doxorubicin, cause DNA damage. However, it remains unknown whether such agents differentially regulate cell cycle arrest in distinct types of B-cell lymphomas, and whether this phenotype can be exploited for developing new therapies. We treated various types of B cells, including primary and B lymphoma cells, with cytarabine or doxorubicin, and determined DNA damage responses, cell cycle regulation and sensitivity to a Wee1 inhibitor. We found that cyclin A2/B1 upregulation appears to be an intrinsic programmed response to DNA damage; however, different types of B cells arrest in distinct phases of the cell cycle. The Wee1 inhibitor significantly enhanced the apoptosis of G2 phase-arrested B-cell lymphomas by inducing premature entry into mitosis and mitotic catastrophe, whereas it did not affect G1/S-phase-arrested lymphomas. Cytarabine-induced G1-arrest can be converted to G2-arrest by doxorubicin treatment in certain B-cell lymphomas, which correlates with newly acquired sensitivity to the Wee1 inhibitor. Consequently, the Wee1 inhibitor together with cytarabine or doxorubicin inhibited tumor growth in vitro and in vivo more effectively, providing a potential new therapy for treating B-cell lymphomas. We propose that the differential cell cycle arrest can be exploited to enhance the chemosensitivity of B-cell lymphomas.
Aging is a gradual, continuous series of natural changes in biological, physiological, immunological, environmental, psychological, behavioral, and social processes. Aging entails changes in the immune system characterized by a decrease in thymic output of naïve lymphocytes, an accumulated chronic antigenic stress notably caused by chronic infections such as cytomegalovirus (CMV), and immune cell senescence with acquisition of an inflammatory senescence-associated secretory phenotype (SASP). For this reason, and due to the SASP originating from other tissues, aging is commonly accompanied by low-grade chronic inflammation, termed “inflammaging”. After decades of accumulating evidence regarding age-related processes and chronic inflammation, the domain now appears mature enough to allow an integrative reinterpretation of old data. Here, we provide an overview of the topics discussed in a recent workshop “Aging and Chronic Inflammation” to which many of the major players in the field contributed. We highlight advances in systematic measurement and interpretation of biological markers of aging, as well as their implications for human health and longevity and the interventions that can be envisaged to maintain or improve immune function in older people.
<b><i>Introduction:</i></b> Centenarians are considered a model of successful aging. Cuba exhibits one of the oldest populations in Latin America with more than two thousand centenarians. <b><i>Methods:</i></b> This study aimed to evaluate the immune phenotype of forty-three Cuban centenarians, their clinical characteristics such as comorbidities, frailty, body mass index, and some hemochemical parameters. <b><i>Results:</i></b> Centenarians had normal body mass indexes, relatively good health status, and 21.95% of them had no comorbidities; 53.6% were classified as frail, and 7% were classified as robust. In addition, 17% of centenarians were independent, and 41.46% were moderately dependent. The seroprevalence against cytomegalovirus was 100%. Concerning pro-inflammatory markers, the majority of them had very low cytokine levels and serum C-reactive protein around the normal limit. We also found the predominance of memory subsets over naive compartments in CD4+ and CD8+ T cells. Terminally differentiated CD8+CD28− T cells were higher in frail centenarians than in pre-frail, while CD8+CD57+ and CD8+EMRA T cells were higher in moderately and severely dependent individuals than in independent individuals. Severely dependent centenarians had a lower CD4+/CD8+ ratio. <b><i>Conclusion:</i></b> This study describes for the first time the predominance of memory subsets over naive compartments in CD4+ and CD8+ T cells, as well as its relation to frailty and/or dependency in a group of Cuban centenarians. Further studies are needed to continue understanding the natural biological aging mechanism and the relationship between terminally differentiated lymphocytes and inflammaging in the context of extreme longevity.
Human papillomaviruses (HPVs) cause over 5% of all human cancer incidences, including a subset of head and neck squamous cell carcinoma (HNSCC), resulting in about half a million deaths every year. Persistent infection with high-risk HPV is necessary for development of HPV-associated malignancies. To establish persistence in the host, HPV must evade host antiviral defenses, including the innate and adaptive immune responses. As antiviral and antitumor immune responses share similar mechanisms, it is likely that HPV-induced immune suppression leads to immune evasion and survival of HPV-infected cancer cells. We have previously shown that expression of the chemokine CXCL14 is significantly downregulated by promoter methylation mediated by the HPV oncoprotein E7 during cancer progression. Restoration of CXCL14 expression in HPV-positive HNSCC cells dramatically suppresses tumor growth through an immune-dependent mechanism in mice. While CXCL14 recruits NK and CD8+ T cells to the tumor microenvironment, the roles of NK and T cells to enact the CXCL14-mediated tumor suppression remained undefined. To determine the roles of NK and CD8+ T cells, tumor growth was assessed in wild-type C57BL/6 mice depleted of NK or CD8+ T cells and CD8-knockout mice injected with the HPV-positive HNSCC cells re-expressing CXCL14. The results show that that CD8+ T cells are required for CXCL14-mediated tumor suppression. The antitumor CD8+ T-cell responses require antigen specificity as a transgenic model of mice with a restricted CD8+ T-cell receptor failed to control tumor growth. Counteracting the HPV-mediated downregulation of major histocompatibility complex class I (MHC-I), CXCL14 expression restores MHC-I expression on HPV-positive HNSCC cells. Furthermore, knockdown of MHC-I expression in CXCL14 expressing HNSCC cells results in loss of tumor suppression, defining a critical role for antigen presentation. These results suggest that CXCL14 expression drives antigen-specific CD8+ T-cell responses and suppresses tumor growth through the restoration of MHC-I expression in HPV-positive HNSCC. Our findings provide useful insight into the CXCL14-mediated antitumor mechanism that increases CD8+ T-cell recognition of tumor cells and could boost the efficacy of current immunotherapies. Citation Format: Joseph A. Westrich, Daniel W. Vermeer, Stephanie Bonney, Alexa Silva, Jennifer N. Berger, Marianna Madeo, Louis Cicchini, John H. Lee, William C. Spanos, Dohun Pyeon. CXCL14-mediated antigen-specific CD8+ T-cell responses suppress HPV-positive head and neck cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A36.
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