المؤلفون: Peng Sun, Peng Wei, Hongliang Liu, Jia Wu, Neil D. Gross, Andrew G. Sikora, Qingyi Wei, Sanjay Shete, Mark E. Zafereo, Jisheng Liu, Guojun Li

المصدر: EBioMedicine, Vol 94, Iss , Pp 104722- (2023)

مصطلحات موضوعية: Telomere length, Recurrence, Genetic variant, Polymorphism, Biomarkers, Human papillomavirus, Medicine, Medicine (General), R5-920

الوصف: Summary: Background: Lymphocyte telomere length (LTL)-related genetic variants may modulate LTL and affect recurrence of squamous cell carcinoma of the oropharynx (SCCOP). Methods: A total of 1013 patients with incident SCCOP were recruited and genotyped for 16 genome-wide association study (GWAS)-identified TL-related polymorphisms. Of these patients, 489 had tumour HPV16 status determination. Univariate and multivariate analyses were performed to evaluate associations. Findings: Of the 16 TL-related polymorphisms, four were significantly associated with LTL: rs1920116, rs3027234, rs6772228, and rs11125529, and the patients with putatively favourable genotypes had approximately 1.5–3 times the likelihood of shorter LTL compared with patients with the corresponding risk genotypes. Moreover, patients with one to four favourable genotypes of the four combined polymorphisms had approximately 3–11 times the likelihood of shorter LTL compared with patients with no favourable genotype. The four LTL-related polymorphisms were significantly associated with approximately 40% reduced risk (for favourable genotypes) or doubled risk (for risk genotypes) of recurrence, and similar but more pronounced associations were observed in patients with tumour HPV16-positive SCCOP. Similarly, patients with one to four risk genotypes had significantly approximately 2.5–4 times increased recurrence risk compared with patients with no risk genotype, and similar but more pronounced associations were observed in patients with tumour HPV16-positive SCCOP. Interpretation: Four LTL-related polymorphisms individually or jointly modify LTL and risk of recurrence of SCCOP, particularly HPV-positive SCCOP. These LTL-related polymorphisms could have potential to further stratify patients with HPV-positive SCCOP for individualized treatment and better survival. Funding: Not applicable.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S2352396423002876; https://doaj.org/toc/2352-3964

URL الوصول: https://doaj.org/article/602af74cf2684e69ba6fac4231735636

المؤلفون: Yifan Xu, Ziqiao Wang, Peng Wei, Richa Gairola, Karl T. Kelsey, Andrew G. Sikora, Guojun Li, Jian Gu

المصدر: Molecular Therapy: Nucleic Acids, Vol 30, Iss , Pp 596-605 (2022)

مصطلحات موضوعية: MT: Non-coding RNAs, oropharyngeal cancer, OPSCC, HPV, DNA methylation, non-coding RNA, Therapeutics. Pharmacology, RM1-950

الوصف: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased rapidly in the United States, driven by rising human papillomavirus (HPV) infections in the U.S. population. HPV-positive OPSCC patients have a better prognosis than HPV-negative patients. To gain insights into the unique biology of HPV(+) OPSCC that may contribute to its clinical behaviors, we performed a multi-stage epigenome-wide methylation profiling of leukocyte and tumor DNA in OPSCC patients and compared the methylation levels of CpG sites between HPV(+) and HPV(−) OPSCC patients. We identified and validated a significantly differentially methylated region (DMR) of 1,355 bp encompassing non-coding RNA 886 (nc886) gene and its promoter region. Nc886 is hypermethylated in both leukocytes and tumor DNA of HPV(+) OPSCC patients. Homozygous knockout of nc886 by CRISPR-Cas9 in head and neck cell lines was lethal, but nc886 could be knocked out on the background of protein kinase R (PKR) knockout. Our data suggest that HPV induces nc886 hypermethylation, and nc886 acts as both a viral sensor and a tumor sensor in OPSCC patients and contribute to the better prognosis of HPV(+) OPSCC patients. Nc886 may become a therapeutic target in OPSCC.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S2162253122003043; https://doaj.org/toc/2162-2531

URL الوصول: https://doaj.org/article/ce1115de010f4b128ef5604551fd3a29

المؤلفون: Yewen Shi, Tongxin Xie, Bingbing Wang, Rong Wang, Yu Cai, Bo Yuan, Frederico O. Gleber-Netto, Xiangjun Tian, Alanis E. Rodriguez-Rosario, Abdullah A. Osman, Jing Wang, Curtis R. Pickering, Xiaoyong Ren, Andrew G. Sikora, Jeffrey N. Myers, Roberto Rangel

المصدر: Communications Biology, Vol 5, Iss 1, Pp 1-14 (2022)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: Oral squamous cell carcinoma models are presented with defined Trp53 mutations associated with immune checkpoint inhibitor responsiveness, e.g. T122N amino acid change of Tp53 promotes a cold TME enriched with immunosuppressive M2 macrophages resistant to ICI therapy.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2399-3642

URL الوصول: https://doaj.org/article/57f97433af1f465f8833d69d49cf18b1

المؤلفون: Hugo Villanueva, Gabrielle A. Wells, Malachi T. Miller, Mariana Villanueva, Ravi Pathak, Patricia Castro, Michael M. Ittmann, Andrew G. Sikora, Seth P. Lerner

المصدر: Heliyon, Vol 8, Iss 12, Pp e12570- (2022)

مصطلحات موضوعية: Bladder cancer, CAM, Proteomics, Genomics, Chemotherapy, Kinase inhibitor, Science (General), Q1-390, Social sciences (General), H1-99

الوصف: Background: Non-metastatic muscle invasive urothelial bladder cancer (MIBC) has a poor prognosis and standard of care (SOC) includes neoadjuvant cisplatin-based chemotherapy (NAC) combined with cystectomy. Patients receiving NAC have at best

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S2405844022038580; https://doaj.org/toc/2405-8440

URL الوصول: https://doaj.org/article/086cef3693b84d1eb141e689ece5ef1d

المؤلفون: Changlin Yang, Rekha Garg, Kristanna Fredenburg, Frances Weidert, Hector Mendez-Gomez, Robert Amdur, Ji-Hyun Lee, Jamie Ku, Jesse Kresak, Stephanie Staras, Andrew G. Sikora, Lily Wang, Daniel McGrail, Duane Mitchell, Elias Sayour, Natalie Silver

المصدر: Cancers, Vol 15, Iss 8, p 2346 (2023)

مصطلحات موضوعية: head and neck cancer, oropharynx cancer, human papillomavirus, myeloid cell, TCGA, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Background: While immune-cell infiltrated tumors, such as human papillomavirus positive (HPV+) ororpharyngeal squamous cell carcinomas (OPSCC) have been associated with an improved clinical prognosis, there is evidence to suggest that OPSCCs are also subjected to increased immunoregulatory influence. The objective of this study was to assess whether patients with clinically aggressive OPSCC have a distinct immunosuppressive immune signature in the primary tumor. Methods: This retrospective case-control study analyzed 37 pre-treatment tissue samples from HPV+ and HPV-negative OPSCC patients treated at a single institution. The cases were patients with known disease recurrence and the controls were patients without disease recurrence. An mRNA-expression immune-pathway profiling was performed, and correlated to clinical outcomes. The TCGA head and neck cancer database was utilized to make comparisons with the institutional cohort. Results: In our cohort, HPV-negative and HPV+ patients with known disease recurrence both had significantly increased suppressive monoctyte/macrophage and granulocyte cell-expression-profile enrichment. Similar findings were found in the TCGA cohort when comparing HPV-negative to positive patients. Conclusions: our study demonstrates that patients with recurrent HPV+ OPSCC had suppressive monocyte/macrophage and granulocyte immune-cell enrichment, similar to those seen in the more aggressive HPV-negative OPSCC.

وصف الملف: electronic resource

Relation: https://www.mdpi.com/2072-6694/15/8/2346; https://doaj.org/toc/2072-6694

URL الوصول: https://doaj.org/article/38f2b24f93c44971acc77093d7ad1628

المؤلفون: Hesham Elhalawani, Abdallah S. R. Mohamed, Baher Elgohari, Timothy A. Lin, Andrew G. Sikora, Stephen Y. Lai, Abdelrahman Abusaif, Jack Phan, William H. Morrison, G. Brandon Gunn, David I. Rosenthal, Adam S. Garden, Clifton D. Fuller, Vlad C. Sandulache

المصدر: BMC Cancer, Vol 20, Iss 1, Pp 1-12 (2020)

مصطلحات موضوعية: Oropharyngeal carcinoma, Radiotherapy, Tobacco, Human papillomavirus, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background The incidence of oropharyngeal squamous cell carcinoma (OPSCC) in the US is rapidly increasing, driven largely by the epidemic of human papillomavirus (HPV)-mediated OPSCC. Although survival for patients with HPV mediated OPSCC (HPV+ OPSCC) is generally better than that of patients with non-virally mediated OPSCC, this effect is not uniform. We hypothesized that tobacco exposure remains a critical modifier of survival for HPV+ OPSCC patients. Methods We conducted a retrospective analysis of 611 OPSCC patients with concordant p16 and HPV testing treated at a single institute (2002–2013). Survival analysis was performed using Kaplan-Meier analysis and Cox regression. Recursive partitioning analysis (RPA) was used to define tobacco exposure associated with survival (p 30 PY patients didn’t differ significantly from HPV- patients (p = 0.72, p = 0.27, respectively). HPV+ > 30 PY patients had substantially lower 5-year OS when compared to their ≤30 PYs counterparts: 78.4% vs 91.6%; p = 0.03, 76% vs 88.3%; p = 0.07, and 52.3% vs 74%; p = 0.05, for stages I, II, and III (AJCC 8th Edition Manual), respectively. Conclusions Tobacco exposure can eliminate the survival benefit associated with HPV+ status in OPSCC patients. Until this effect can be clearly quantified using prospective datasets, de-escalation of treatment for HPV + OPSCC smokers should be avoided.

وصف الملف: electronic resource

Relation: http://link.springer.com/article/10.1186/s12885-020-07427-7; https://doaj.org/toc/1471-2407

URL الوصول: https://doaj.org/article/9bd8ba72b9aa492cadec555e64a4ee09

المؤلفون: Roberto Rangel, Curtis R. Pickering, Andrew G. Sikora, Michael T. Spiotto

المصدر: Frontiers in Immunology, Vol 13 (2022)

مصطلحات موضوعية: head and neck cancer, immunosuppression, TP53, CDKN2A, NOTCH1, Immunologic diseases. Allergy, RC581-607

الوصف: Oral premalignant lesions (OPLs) are the precursors to oral cavity cancers, and have variable rates of progression to invasive disease. As an intermediate state, OPLs have acquired a subset of the genomic alterations while arising in an oral inflammatory environment. These specific genomic changes may facilitate the transition to an immune microenvironment that permits malignant transformation. Here, we will discuss mechanisms by which OPLs develop an immunosuppressive microenvironment that facilitates progression to invasive cancer. We will describe how genomic alterations and immune microenvironmental changes co-evolve and cooperate to promote OSCC progression. Finally, we will describe how these immune microenvironmental changes provide specific and unique evolutionary vulnerabilities for targeted therapies. Therefore, understanding the genomic changes that drive immunosuppressive microenvironments may eventually translate into novel biomarker and/or therapeutic approaches to limit the progression of OPLs to potential lethal oral cancers.

وصف الملف: electronic resource

Relation: https://www.frontiersin.org/articles/10.3389/fimmu.2022.840923/full; https://doaj.org/toc/1664-3224

URL الوصول: https://doaj.org/article/4c8eb37d4bd44b0aaa250cdac0db8217

المؤلفون: Vlad C. Sandulache, David C. Wilde, Erich M. Sturgis, Elizabeth Y. Chiao, Andrew G. Sikora

المصدر: Laryngoscope Investigative Otolaryngology, Vol 4, Iss 6, Pp 617-623 (2019)

مصطلحات موضوعية: Oropharynx, HPV, tobacco, radiation, tumor immune microenvironment, Otorhinolaryngology, RF1-547, Surgery, RD1-811

الوصف: Objectives Oropharyngeal squamous cell carcinoma (OPSCC) incidence is rapidly increasing in the United States and around the world, driven in large part by infection with the human papillomavirus (HPV). HPV associated OPSCC (HPV+OPSCC) has been shown to have improved response to treatment relative to tobacco‐associated OPSCC. However, improvement in patient survival has not been uniform. Subsets of OPSCC patients in the US and around the world continue to have poor oncologic outcomes. Although the drivers of this phenomenon remain unclear, there is increasing evidence that tobacco exposure plays an important role in modulating HPV+OPSCC clinical outcomes. Methods We conducted a review of the literature. Results We discuss the potential biological and epidemiological interplay between tobacco and HPV exposure in the context of OPSCC. Multiple retrospective and prospective cohorts show that HPV+OPSCC patients with a history of tobacco exposure have response to treatment and clinical outcomes distinct from HPV+OPSCC non‐smokers which poses clinical and scientific challenges to be addressed over the next decade. Conclusions The interaction between tobacco exposure and HPV infection in the context of OPSCC has significant implications for both standard of care treatment regimens and development of novel therapeutic approaches, in particular those which incorporate immunomodulatory agents. Level of Evidence 5

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2378-8038

URL الوصول: https://doaj.org/article/94541377c0fd4c47ad7f54bba811ee7b

المؤلفون: Jared M. Newton, Aurelie Hanoteau, Hsuan-Chen Liu, Angelina Gaspero, Falguni Parikh, Robyn D. Gartrell-Corrado, Thomas D. Hart, Damya Laoui, Jo A. Van Ginderachter, Neeraja Dharmaraj, William C. Spanos, Yvonne Saenger, Simon Young, Andrew G. Sikora

المصدر: Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-21 (2019)

مصطلحات موضوعية: Immunotherapy, Tumor immune microenvironment, Immune checkpoint inhibitors, Programmed cell death protein-1 (PD-1), Cytotoxic T lymphocyte associated antigen-4 (CTLA-4), Cyclophosphamide (CTX), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Immune checkpoint inhibitors (ICIs) for solid tumors, including those targeting programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), have shown impressive clinical efficacy, however, most patients do not achieve durable responses. One major therapeutic obstacle is the immunosuppressive tumor immune microenvironment (TIME). Thus, we hypothesized that a strategy combining tumor-directed radiation with TIME immunomodulation could improve ICI response rates in established solid tumors. Methods Using a syngeneic mouse model of human papillomavirus (HPV)-associated head and neck cancer, mEER, we developed a maximally effective regimen combining PD-1 and CTLA-4 inhibition, tumor-directed radiation, and two existing immunomodulatory drugs: cyclophosphamide (CTX) and a small-molecule inducible nitric oxide synthase (iNOS) inhibitor, L-n6-(1-iminoethyl)-lysine (L-NIL). We compared the effects of the various combinations of this regimen on tumor growth, overall survival, establishment of immunologic memory, and immunologic changes with flow cytometry and quantitative multiplex immunofluorescence. Results We found PD-1 and CTLA-4 blockade, and radiotherapy alone or in combination, incapable of clearing established tumors or reversing the unfavorable balance of effector to suppressor cells in the TIME. However, modulation of the TIME with cyclophosphamide (CTX) and L-NIL in combination with dual checkpoint inhibition and radiation led to rejection of over 70% of established mEER tumors and doubled median survival in the B16 melanoma model. Anti-tumor activity was CD8+ T cell-dependent and led to development of immunologic memory against tumor-associated HPV antigens. Immune profiling revealed that CTX/L-NIL induced remodeling of myeloid cell populations in the TIME and tumor-draining lymph node and drove subsequent activation and intratumoral infiltration of CD8+ effector T cells. Conclusions Overall, this study demonstrates that modulation of the immunosuppressive TIME is required to unlock the benefits of ICIs and radiotherapy to induce immunologic rejection of treatment-refractory established solid tumors.

وصف الملف: electronic resource

Relation: http://link.springer.com/article/10.1186/s40425-019-0698-6; https://doaj.org/toc/2051-1426

URL الوصول: https://doaj.org/article/5865ba33af83434c8d59aa844ab92960

المؤلفون: Aurelie Hanoteau, Jared M. Newton, Rosemarie Krupar, Chen Huang, Hsuan-Chen Liu, Angelina Gaspero, Robyn D. Gartrell, Yvonne M. Saenger, Thomas D. Hart, Saskia J. Santegoets, Damya Laoui, Chad Spanos, Falguni Parikh, Padmini Jayaraman, Bing Zhang, Sjoerd H. Van der Burg, Jo A. Van Ginderachter, Cornelis J. M. Melief, Andrew G. Sikora

المصدر: Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-19 (2019)

مصطلحات موضوعية: Immunotherapy, Tumor microenvironment, Inducible nitric oxide synthase (iNOS), Cyclophosphamide, L-n6-(1-iminoethyl)-lysine (L-NIL), Chemoradiotherapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Chemoradiotherapy (CRT) remains one of the most common cancer treatment modalities, and recent data suggest that CRT is maximally effective when there is generation of an anti-tumoral immune response. However, CRT has also been shown to promote immunosuppressive mechanisms which must be blocked or reversed to maximize its immune stimulating effects. Methods Therefore, using a preclinical model of human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC), we developed a clinically relevant therapy combining CRT and two existing immunomodulatory drugs: cyclophosphamide (CTX) and the small molecule inducible nitric oxide synthase (iNOS) inhibitor L-n6-(1-iminoethyl)-lysine (L-NIL). In this model, we treated the syngeneic HPV-HNSCC mEER tumor-bearing mice with fractionated (10 fractions of 3 Gy) tumor-directed radiation and weekly cisplatin administration. We compared the immune responses induced by CRT and those induced by combinatory treatment (CRT + CTX/L-NIL) with flow cytometry, quantitative multiplex immunofluorescence and by profiling immune-related gene expression changes. Results We show that combination treatment favorably remodels the tumor myeloid immune microenvironment including an increase in anti-tumor immune cell types (inflammatory monocytes and M1-like macrophages) and a decrease in immunosuppressive granulocytic myeloid-derived suppressor cells (MDSCs). Intratumoral T cell infiltration and tumor antigen specificity of T cells were also improved, including a 31.8-fold increase in the CD8+ T cell/ regulatory T cell ratio and a significant increase in tumor antigen-specific CD8+ T cells compared to CRT alone. CTX/LNIL immunomodulation was also shown to significantly improve CRT efficacy, leading to rejection of 21% established tumors in a CD8-dependent manner. Conclusions Overall, these data show that modulation of the tumor immune microenvironment with CTX/L-NIL enhances susceptibility of treatment-refractory tumors to CRT. The combination of tumor immune microenvironment modulation with CRT constitutes a translationally relevant approach to enhance CRT efficacy through enhanced immune activation.

وصف الملف: electronic resource

Relation: http://link.springer.com/article/10.1186/s40425-018-0485-9; https://doaj.org/toc/2051-1426

URL الوصول: https://doaj.org/article/529ee5858b424de6b4b551d4e3d1d450