PD‑L1 expression is associated with p16INK4A expression in non‑oropharyngeal head and neck squamous cell carcinoma
- Authors:
- Published online on: December 8, 2017 https://doi.org/10.3892/ol.2017.7564
- Pages: 2259-2265
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Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Head and neck squamous cell carcinoma (HNSCC), the sixth most common type of cancer in the world, occurs at various sites, including the oral cavity, oropharynx, hypopharynx and larynx (1). The most common risk factors for HNSCC are tobacco use, betel quid chewing, alcohol consumption and human papillomavirus (HPV) infection (2). Previous studies have identified the distinct etiologies of HNSCC arising from different anatomical locations (3,4). In cancer arising from the oropharynx, such as oropharyngeal squamous cell carcinoma (OPSCC), HPV is the major causative factor and it has been reported that the expression of p16INK4A, an important tumor suppressor protein encoded by the cyclin dependent kinase inhibitor 2A (CDKN2A) gene, is a biomarker for HPV infection and indicates good patient prognosis (5). By contrast, in cancer arising from the non-oropharyngeal head and neck region, such as non-oropharyngeal head and neck squamous cell carcinoma (non-OPHNSCC), the roles of HPV infection and p16INK4A expression have not been clearly defined. The causes of non-OPHNSCC may be complex as environmental carcinogens, including alcohol, tobacco and betel quid serve a role in tumor initiation and progression (6). It has been demonstrated that p16INK4A expression is a poor surrogate biomarker of HPV infection (7) and is controversial for its prognostic value in non-OPHNSCC (8). In Taiwan, a country with a high prevalence of betel quid chewing, the predictive value of p16INK4A expression for HPV infection in non-OPHNSCC is low (9).
Inflammatory tumor microenvironments contribute to the carcinogenesis and progression of HNSCC (10); however, few studies have investigated the association between p16INK4A expression and tumor inflammation or immunity. An association between p16INK4A and inflammatory factors has been identified. A previous study demonstrated that the expression of p16INK4A may be inhibited by Toll-like receptors (11). Furthermore, the expression of alternate reading frame protein, which is associated with macrophages surrounding the tumor, is correlated with p16INK4A expression in pancreatic cancer (12). In addition, environmental carcinogens damage normal mucosal cells in the upper aerodigestive tract due to repeated inflammation and are correlated with gene polymorphisms including CTLA4 or TNFα that are important in determining the prognosis of patients with HNSCC (13,14). However, the role of p16INK4A in non-OPHNSCC remains unclear.
Programmed cell death 1-ligand 1 (PD-L1) is an immune modulatory molecule in cancer cells that inhibits cytotoxic T cell activity (15). The expression of PD-L1, which belongs to the B7 superfamily of proteins, can be induced in certain types of solid and hematological cancer. PD-L1 binds to programmed cell death protein 1 (PD-1) and cluster of differentiation 80 in T cells in the tumor microenvironment to modulate immunity. This is one of the mechanisms by which cancer cells evade the immune system (16). In non-OPHNSCC, interferon (INF)-α induces PD-L1 expression in cancer cells via the protein kinase D isoform 2 (PKD2) pathway to evade recognition by tumor antigen specific T cells (17). Studies have identified varying levels of PD-L1 expression in human HNSCC tissues, ranging from 40–100%; however, most of the data available pertain to OPSCC (18–20). PD-L1 expression may cause immune evasion of HPV, which in turn leads to malignant transformation. Furthermore, it has been reported that HPV-positive patients exhibit a higher expression of PD-L1 than HPV-negative patients with OPSCC (19). However, in patients with non-OPHNSCC, the expression of PD-L1 and p16INK4A, as well as their association, remains unclear. Furthermore, the prognostic value of PD-L1 in HNSCC has not been clearly established, as its expression may not reflect the fluid interactions of PD-L1 to the dynamic immune response in the tumor microenvironment (21). To the best of our knowledge, the current study is the first to evaluate the expression of PD-L1 in non-OPHNSCC and its association with p16INK4A expression, as well as other clinicopathological characteristics. The prognostic role of PD-L1 was also evaluated.
Patients and methods
Patients
Between January 2007 and August 2014, 106 patients with non-OPHNSCC that was pathologically proven, at the Taipei Veterans General Hospital (Taipei, Taiwan) were retrospectively reviewed. Information regarding patient characteristics, including patient age, sex, history of betel quid chewing, tobacco use, alcohol consumption and treatment history was collected. Information about the pathological characteristics of perineural invasion, lymphovascular invasion, tumor emboli and extra-capsular spread was also collected. Cancer staging was established according to the 7th American Joint Committee on Cancer Staging Manual (22). The current study was approved by The Institutional Review Board of Taipei Veterans General Hospital (TVGHTPE-2017-08-002BC). Since the current study was retrospective, patient consent was waived.
Immunohistochemical (IHC) staining of PD-L1 and p16INK4A
Tissue arrays (depth of 1.5 mm) were constructed as described previously (23). Xylene was used to deparaffinize the samples and serial dilutions of alcohol (100, 95, 75 and 50%) were used to rehydrate the array samples. Antigen retrieval was performed by placing samples in a citrate buffer (pH 6.0) and heating to 121°C in an autoclave for 10 min. Following this, samples were bathed in the blocking agent, 3% bovine serum albumin (BSA), for 30 min at room temperature. Samples were then incubated overnight at 4°C with primary antibodies, anti-PD-L1 (cat. no. 13684S; dilution, 1:200; Cell Signaling Technology, Inc., Danvers, MA, USA) and a monoclonal anti-mouse p16INK4A (cat. no. sc-81157; dilution, 1:100; Santa Cruz Biotechnology, Inc., Dallas, TX, USA). By using MultiLink + HRP label kits (Super Sensitive™ IHC Detection Systems; BioGenex Laboratories, Inc., Fremont, CA, USA), samples were incubated with secondary antibody (a mix of anti-mouse and anti-rabbit IgGs conjugated to multiple biotin molecules) for 20 min at room temperature. Subsequently, a horseradish peroxidase (HRP)-conjugated streptavidin solution (Streptavidin/HRP complex; Multi-Link Biogenex, BioGenex Laboratories) was used for incubation for 20 min at room temperature. AEC substrates (cat. no. HK139-50K; ready to use; BioGenex Laboratories, CA, USA) was used for staining for 2 min at room temperature and the tissues were counterstained with hematoxylin for 1 min at room temperature. The sections were then examined by a light microscope (Eclipse 80i; Nikon Corporation, Tokyo, Japan).
Tumor cells exhibiting membranous and cytoplasmic staining were defined as positive for PD-L1 and those exhibiting nuclear and cytoplasmic staining were defined as positive for p16INK4A. The distribution of staining was categorized as follows: 0, 0–5% staining; 1+, 5–20% staining; 2+, 20–50%; 3+, ≥51%. Cases were classified binarily as positive for PD-L1 when there was staining >5% (1+, 2+ and 3+) of cancer cells (20,24) and positive for p16INK4A when staining was >20% (2+ and 3+) (25). Staining was analyzed by two independent investigators (five random fields at magnification, ×200).
Statistical analysis
The Mann-Whitney test was used to compare continuous variables and the χ2 or Fisher's exact test was used to compare categorical variables between groups. Progression-free survival (PFS) was defined as the time period from diagnosis until disease progression. Overall survival (OS) was calculated from the time of diagnosis to mortality. Cox proportional analysis was also used to determine risk factors for disease progression and mortality. The log-rank test to compare Kaplan-Meier curves. P<0.05 was considered to indicate a statistically significant difference.
Results
Patient clinicopathological characteristics
Of the 106 patients with non-OPHNSCC, there were 99 (93.4%) males and 7 (6.6%) females, with a mean age of 58.8±11.5 years. The tumor sites included the oral cavity (63.2%), hypopharynx (27.4%) and larynx (9.4%). A total of 33 patients (31.1%) were diagnosed as having stage I/II disease and 73 (68.9%) had stage III/IV disease. With respect to risk factors for HNSCC, 55 (51.9%) patients partook in chewing betel quid, 84 (79.2%) had used tobacco and 66 (62.3%) consumed alcohol. Regarding treatment, 40 (37.7%) patients received radical surgery alone and 50 (47.2%) patients received surgery followed by adjuvant therapy, consisting of chemotherapy (cisplatin 25 mg/m2 IV weekly plus tegafur-uracil 400 mg daily for up to 7 weeks), radiotherapy (60–66 Gy) and concurrent chemoradiotherapy. A total of 16 (15.1%) patients received definitive chemoradiotherapy (cisplatin 80 mg/m2 on day 1 plus 5-fluorouracil 400 mg/m2/day by continuous infusion on days 1–4, every 28 days for 2 cycles plus radiation 66–72 Gy); whereas 10 (9.4%) were administered induction chemotherapy (cisplatin 80 mg/m2 on day 1 plus 5-fluorouracil 600 mg/m2/day by continuous infusion on days 1–4 every 28 days for 2 cycles; or docetaxel 60 mg/m2 plus cisplatin 75 mg/m2 on day 1 plus 5-fluorouracil 850 mg/m2/day by continuous infusion on days 1–4 every 28 days for 2 cycles; Table I). A total of 34 patients (32.1%) exhibited PD-L1 expression (Fig. 1A and B) and 22 (20.8%) exhibited p16INK4A expression (Fig. 1C and D).
Association between PD-L1 expression and clinicopathological characteristics
Positive p16INK4A expression was significantly higher in the group exhibiting positive expression of PD-L1 compared with the group exhibiting negative expression of PD-L1 (38.2 vs. 12.5%; P<0.01; Table II). Furthermore, the mean age of patients exhibiting positive PD-L1 expression was significantly higher than those exhibiting negative PD-L1 expression (62.5±10.4 vs. 57.0±11.7; P<0.01; Table II). However, positive PD-L1 expression was not associated with clinical stage, oral habits or primary cancer sites (Table II). Since it has been demonstrated that PD-L1 is associated with the inflammatory tumor microenvironment (26), the association between PD-L1 and systemic inflammatory factors at diagnosis, including total white blood cell count, absolute neutrophil count, absolute lymphocyte count, absolute monocyte count, neutrophils/lymphocyte ratio and C-reactive protein levels, were investigated. However, there was no significant association between PD-L1 expression and any of the aforementioned inflammatory factors (Table II).
Risk factors for PFS and OS
Univariate Cox proportional hazards analysis demonstrated that only advanced cancer stage (III, IV) was a prognostic factor of OS (HR, 7.53; P=0.05). Neither oral habits, nor pathological characteristics, including PD-L1 and p16INK4A expression, were risk factors for disease progression and survival (Table III). Following adjustment for cancer stage, PD-L1 and p16INK4A expression did not qualify as independent risk factors.
Patients with early stage cancer (I or II) had a significantly better survival rate (P<0.05) than those with advanced stage cancer (III or IV; Fig. 2A). However, the differing status of PD-L1 and p16INK4A expression did not significantly affect the OS of patients (Fig. 2B and C).
Discussion
The results of the current study demonstrate that PD-L1 is expressed in a proportion of patients with non-OPHNSCC and that PD-L1 expression is significantly associated with p16INK4A expression. However, PD-L1 expression is not a prognostic factor for non-OPHNSCC. In the current study, 32.1% of subjects exhibited positive PD-L1 expression, comparable to the results of previous studies, which demonstrated that positive PD-L1 expression occurred in 19–66% of HNSCC cases (18,24,27) and 46–59% in OPSCC cases (19,20). Positive expression of PD-L1 was observed in 50% of larynx squamous cell carcinoma cases, a relatively high proportion, however the number of cases included in this study was relatively small (28). The variation in the level of PD-L1 expression may be attributed to the heterogeneity of subjects, a small sample size and the inclusion of different ethnic groups. In the current study, analysis of the levels of systemic inflammation factors demonstrated that they were not associated with PD-L1 expression, suggesting that the tumor microenvironment, not systemic inflammation, is an important factor influencing tumor immune evasion. The identification of PD-L1 has led to the development of PD-L1 antibodies to treat types of cancer that were previously considered to be immune-responsive, including non-small cell lung cancer and HNSCC (24). The results of the current study may provide information that may be important in the investigation of immune checkpoint blockage in non-OPHNSCC.
In the present study, it was demonstrated that there was an association between PD-L1 and p16INK4A expression in cancer cells, which may be explained by the response of cancer cells to immune attack. It has been demonstrated that IFN-γ produced by inflammatory cells in the tumor microenvironment directly induces p16INK4A expression and downstream retinoblastoma (Rb) protein hypophosphorylation in cancer cells, which leads to permanent growth arrest in tumors (29). This may be a general mechanism for arresting tumor progression. By contrast, in OPSCC, it has been suggested that p16INK4A expression is caused by HPV infection that results in the inactivation by Rb by E7 oncoprotein (30). Furthermore, in non-OPHNSCC, IFN-γ induces cancer cells to express PD-L1 via the PKD2 pathway (17). Similar results have been reported in ovarian cancer, where IFN-γ stimulated PD-L1 expression, thus promoting tumor progression (31). The results of the current study identified the co-occurrence of senescence and immune evasion of cancer cells, which may be used to develop novel agents targeting non-OPHNSCC in the future.
It remains unknown whether PD-L1 expression is associated with cancer stage and patient prognosis. The present study demonstrated that PD-L1 expression is not associated with non-OPHNSCC stage or sites of occurrence, which is in accordance with the results of previous studies. Ukpo et al (20) reported that PD-L1 expression is not associated with nodal disease and tumor-node-metastasis stage. With regards to prognosis, previous studies have indicated that there is no correlation of survival rate with PD-L1 expression in oral squamous cell carcinoma (20,28), which is consistent with the results of the present study. The association between PD-L1 expression and patient outcomes is controversial; it has been demonstrated in lung cancer that PD-L1 expression is correlated with an improved outcome (32), however, this has not been the case in the other study (33). Such discrepancies may be due to the complex interactions that occur between tumor and immune cells in the tumor microenvironment. It has previously been established that PD-L1 expression helps cancer cells to evade immune attack, which may lead to tumor progression and poorer patient outcomes. However, the co-expression of PD-L1 and p16INK4A may attenuate tumor growth and turn tumor cells into senescent cells, offsetting tumor aggression. Furthermore, immune evasion is not only determined by upregulation of PD-L1 but also by PD-1 expression in tumor-infiltrating T cells (18). Due to these factors, PD-L1 expression cannot be used as a prognostic factor in non-OPHNSCC.
There were several limitations of the present study. Although a significant association between PD-L1 and p16INK4A expression was identified, the mechanism between immune checkpoint and senescence remains unclear. As well as the immune response, the expression of other genes or proteins may affect the expression of PD-L1 (34) and p16INK4A (35). In addition, the patients included in the current study underwent different treatment strategies due to differences in cancer stage, which is a common selection bias of retrospective studies. Although adjustments for cancer stage were made, this bias may not have been fully corrected. Finally, there is no standard cutoff value of IHC expression to define PD-L1 and p16 positive. Having a different cutoff value may generate inconsistent results and further studies are required to establish standard values.
In conclusion, the present study identified an association between PD-L1 and p16INK4A expression in non-OPHNSCC. The poor association between PD-L1 expression and clinical and prognostic status highlight the complex interactions between the tumor and its microenvironment. Further investigations into cancer cell senescence and immune evasion in microenvironment are required.
Acknowledgements
The current study was supported by the Ministry of Science and Technology (103-2314-B-010-034-MY3 to M.-H.Y.), Taipei Veterans General Hospital (V104-E8-001 to M,-H.Y.) and a grant from Ministry of Health and Welfare, Center of Excellence for Cancer Research (MOHW104-TDU-B-211-124-001 to P.-Y.C.). The current study was partly assisted by the Division of Experimental Surgery, Department of Surgery of Taipei Veterans General Hospital. The authors would like to acknowledge the support by the Biobank of Taipei Veterans General Hospital. The abstract of the current study was presented at the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium in Orlando, US on Feb 24, 2017.
References
|
Warnakulasuriya S: Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 45:309–316. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Kreimer AR, Clifford GM, Boyle P and Franceschi S: Human papillomavirus types in head and neck squamous cell carcinomas worldwide: A systematic review. Cancer Epidemiol Biomarkers Prev. 14:467–475. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Leemans CR, Braakhuis BJ and Brakenhoff RH: The molecular biology of head and neck cancer. Nat Rev Cancer. 11:9–22. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, Westra WH, Chung CH, Jordan RC, Lu C, et al: Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 363:24–35. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Rischin D, Young RJ, Fisher R, Fox SB, Le QT, Peters LJ, Solomon B, Choi J, O'Sullivan B, Kenny LM and McArthur GA: Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol. 28:4142–4148. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Hashibe M, Brennan P, Benhamou S, Castellsague X, Chen C, Curado MP, Dal Maso L, Daudt AW, Fabianova E, Fernandez L, et al: Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: Pooled analysis in the international head and neck cancer epidemiology consortium. J Natl Cancer Inst. 99:777–489. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Smith EM, Wang D, Kim Y, Rubenstein LM, Lee JH, Haugen TH and Turek LP: P16INK4a expression, human papillomavirus, and survival in head and neck cancer. Oral Oncol. 44:133–142. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Salazar CR, Anayannis N, Smith RV, Wang Y, Haigentz M Jr, Garg M, Schiff BA, Kawachi N, Elman J, Belbin TJ, et al: Combined P16 and human papillomavirus testing predicts head and neck cancer survival. Int J Cancer. 135:2404–2412. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Chen SF, Yu FS, Chang YC, Fu E, Nieh S and Lin YS: Role of human papillomavirus infection in carcinogenesis of oral squamous cell carcinoma with evidences of prognostic association. J Oral Pathol Med. 41:9–15. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Grivennikov SI, Greten FR and Karin M: Immunity, inflammation, and cancer. Cell. 140:883–899. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Ochi A, Graffeo CS, Zambirinis CP, Rehman A, Hackman M, Fallon N, Barilla RM, Henning JR, Jamal M, Rao R, et al: Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans. J Clin Invest. 122:4118–4129. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Través PG, Luque A and Hortelano S: Macrophages, inflammation, and tumor suppressors: ARF, a new player in the game. Mediators Inflamm. 2012:5687832012. View Article : Google Scholar : PubMed/NCBI | |
|
Wong YK, Chang KW, Cheng CY and Liu CJ: Association of CTLA-4 gene polymorphism with oral squamous cell carcinoma. J Oral Pathol Med. 35:51–54. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Liu CJ, Wong YK, Chang KW, Chang HC, Liu HF and Lee YJ: Tumor necrosis factor-alpha promoter polymorphism is associated with susceptibility to oral squamous cell carcinoma. J Oral Pathol Med. 34:608–612. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Dong H, Zhu G, Tamada K and Chen L: B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 5:1365–1369. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, et al: Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nat Med. 8:793–800. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Chen J, Feng Y, Lu L, Wang H, Dai L, Li Y and Zhang P: Interferon-γ-induced PD-L1 surface expression on human oral squamous carcinoma via PKD2 signal pathway. Immunobiology. 217:385–393. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Badoual C, Hans S, Merillon N, Van Ryswick C, Ravel P, Benhamouda N, Levionnois E, Nizard M, Si-Mohamed A, Besnier N, et al: PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. 73:128–138. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH, Akpeng B, Bruno TC, Richmon JD, Wang H, Bishop JA, et al: Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 73:1733–1741. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Ukpo OC, Thorstad WL and Lewis JS Jr: B7-H1 expression model for immune evasion in human papillomavirus-related oropharyngeal squamous cell carcinoma. Head Neck Pathol. 7:113–121. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Zandberg DP and Strome SE: The role of the PD-L1:PD-1 pathway in squamous cell carcinoma of the head and neck. Oral Oncol. 50:627–632. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Edge SB and Compton CC: The American Joint Committee on Cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 17:1471–1474. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Chen YW, Kao SY and Yang MH: Analysis of p16(INK4A) expression of oral squamous cell carcinomas in Taiwan: Prognostic correlation without relevance to betel quid consumption. J Surg Oncol. 106:149–154. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, et al: Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 515:563–567. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Chen YW, Kao SY, Wang HJ and Yang MH: Histone modification patterns correlate with patient outcome in oral squamous cell carcinoma. Cancer. 119:4259–4267. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T and Minato N: Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA. 99:pp. 12293–12297. 2002; View Article : Google Scholar : PubMed/NCBI | |
|
Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, Salomao D, Cheville J, Hirano F, Lin W, et al: B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 63:6501–6505. 2003.PubMed/NCBI | |
|
Cho YA, Yoon HJ, Lee JI, Hong SP and Hong SD: Relationship between the expressions of PD-L1 and tumor-infiltrating lymphocytes in oral squamous cell carcinoma. Oral Oncol. 47:1148–4253. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Braumüller H, Wieder T, Brenner E, Aßmann S, Hahn M, Alkhaled M, Schilbach K, Essmann F, Kneilling M, Griessinger C, et al: T-helper-1-cell cytokines drive cancer into senescence. Nature. 494:361–365. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Parry D, Bates S, Mann DJ and Peters G: Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product. Embo J. 14:503–511. 1995.PubMed/NCBI | |
|
Abiko K, Matsumura N, Hamanishi J, Horikawa N, Murakami R, Yamaguchi K, Yoshioka Y, Baba T, Konishi I and Mandai M: IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br J Cancer. 112:1501–1509. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, Herbst RS, Gettinger SN, Chen L and Rimm DL: Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest. 94:107–116. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H and Nishimura M: B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res. 10:5094–5100. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Zhu J, Chen L, Zou L, Yang P, Wu R, Mao Y, Zhou H, Li R, Wang K, Wang W, et al: MiR-20b, −21, and −130b inhibit PTEN expression resulting in B7-H1 over-expression in advanced colorectal cancer. Hum Immunol. 75:348–353. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Sage J, Miller AL, Pérez-Mancera PA, Wysocki JM and Jacks T: Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature. 424:223–228. 2003. View Article : Google Scholar : PubMed/NCBI |
