Recent years have seen a renaissance in the research linking inflammation and cancer with immune cells playing a central role in smouldering inflammation in the tumor microenvironment. Diverse immune cell types infiltrate the tumor microenvironment, and the dynamic tumor-immune cell interplay gives rise to a rich milieu of cytokines and growth factors. Fundamentally, this intricate cross-talk creates the conducive condition for tumor cell proliferation, survival and metastasis. Interestingly, the prominent impact of immune cells is expounded in their contrary pro-tumoral role, as well as their potential anti-cancer cellular weaponry. The latter is known as immunotherapy, a concept born out of evidence that tumors are susceptible to immune defence and that by manipulating the immune system, tumor growth can be successfully restrained. Naturally, a deeper understanding of the multifaceted roles of various immune cell types thus contributes toward developing innovative anti-cancer strategies. Therefore, in this review we first outline the roles played by the major immune cell types, such as macrophages, neutrophils, natural killer cells, T cells and B cells. We then explain the recently-explored strategies of immunomodulation and discuss some important approaches via an immunology perspective.

Targeting immune cells for cancer therapy.

Cervical cancer is one of the most common gynecological tumors, and the majority of early-stage cervical cancer patients achieve good recovery through surgical treatment and concurrent chemoradiotherapy (CCRT). However, for patients with recurrent, persistent, metastatic cervical cancer, effective treatment is rare, except for bevacizumab combined with chemotherapy. Programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors might be a novel choice to improve the clinical outcomes of these patients. Thus far, some pivotal trials, including Keynote 028, Keynote 158 and Checkmate 358, have indicated established clinical benefit of PD-1/PD-L1 inhibitors in cervical cancer. In light of these data, the FDA has approved pembrolizumab for patients with recurrent or metastatic cervical cancer with disease progression during or after chemotherapy. There are also some ongoing studies that may provide more evidence for the PD-1/PD-L1 pathway as a therapeutic target in cervical cancer. In this review, we have summarized the status and application of PD-1/PD-L1 inhibitors in clinical trials for the treatment of cervical cancer and suggested some future directions in this field.

/pdf/pd-1-pd-l1-inhibitors-in-cervical-cancer-1totaa19x4.pdf

PD-1/PD-L1 Inhibitors in Cervical Cancer

PURPOSE No combined immunotherapy and antiangiogenic therapy have been investigated in exclusively programmed death-ligand 1 (PD-L1)–positive advanced cervical cancer (CA). We investigated the efficacy and safety of sintilimab plus anlotinib as second-line or later therapy for PD-L1–positive recurrent or metastatic (R/M) CA. PATIENTS AND METHODS Patients with PD-L1–positive (Combined Positive Score ≥ 1) R/M CA who progressed after at least one prior systemic chemotherapeutic regimen or could not tolerate chemotherapy were eligible for the phase II trial. The patients received 200 mg sintilimab once on day 1 and 10 mg anlotinib once daily on days 1-14 every 3 weeks. The primary end point was investigator-confirmed objective response rate (ORR) per RECIST v1.1. Secondary end points included progression-free survival (PFS), overall survival, and disease control rate. Biomarkers were explored. RESULTS Forty-two patients were enrolled. The ORR was 54.8% (95% CI, 38.7 to 70.2). In 39 efficacy-evaluable patients, the ORR was 59.0% (95% CI, 42.1 to 74.4); the disease control rate was 94.9% (95% CI, 82.7 to 99.4). The median PFS was 9.4 months (95% CI, 8.0 to 14.6). The median overall survival was not reached. Furthermore, 85.8% of the patients experienced treatment-related adverse events. The most frequent treatment-related adverse events were hypothyroidism (33.3%), elevated aspartate aminotransferase levels (21.4%), and hypertension (19.0%). Patients with altered PIK3CA, PI3K-AKT signaling, or KMT2D had a higher ORR, whereas those with altered STK11 and/or JAK2 had a significantly shorter PFS. CONCLUSION Sintilimab plus anlotinib as second-line or later therapy is efficacious and safe for patients with advanced CA who have failed prior chemotherapy. 

Efficacy and Safety of Sintilimab Plus Anlotinib for PD-L1–Positive Recurrent or Metastatic Cervical Cancer: A Multicenter, Single-Arm, Prospective Phase II Trial

Skull base chordomas account for less than 0.2% and chondrosarcomas for less than 0.15% of all intracranial tumors. Although their clinical and imaging presentations are similar, they derive from different origins. Chordomas arise from embryonic remnants of the primitive notochord and chondrosarcomas from primitive mesenchymal cells or from the embryonic rest of the cranial cartilaginous matrix. Both entities are characterized by infiltration and destruction of the surrounding bone and soft tissue and a high locoregional recurrence rate. Chondrosarcomas, when treated with similar complex strategies, display a much better prognosis than chordomas. The overall survival is approximately 65% for chordomas and 80% for chondrosarcomas at 5 years and 30 and 50%, respectively, at 10 years. Chordomas are divided into the following 3 histological types: classical (conventional), chondroid, and dedifferentiated. Chondrosarcomas have conventional, mesenchymal, clear cell, and dedifferentiated subgroups. Both tumor entities often present with nonspecific symptoms, and headaches are the most reported initial symptom. Computed tomography and magnetic resonance imaging are required to determine the tumor localization and the extent of tumor growth. The treatment philosophy is to maximize tumor resection, minimize morbidity, and preserve function. Neurosurgical approaches commonly used for the resection of intracranial chordomas and chondrosarcomas are transsphenoidal, transbasal, cranio-orbitozygomatic, transzygomatic extended middle fossa, transcondylar, and transmaxillary approaches. Chordomas and chondrosarcomas are not sensitive to chemotherapy and there are no approved drugs for their treatment. The present treatment concept is a combination of surgical resection with a maximal excision and preserving patients' quality of life by adjuvant radiotherapy for both chordomas and chondrosarcomas.

/pdf/skull-base-chordomas-and-chondrosarcomas-2xfh593tuu.pdf

Skull Base Chordomas and Chondrosarcomas.

Resistance to chemotherapy is widely recognized as one of the major factors limiting therapeutic efficacy and influences clinical outcomes in patients with cancer. Many studies on various tumor types have focused on combining standard-of-care chemotherapy with immunotherapy. However, for cervical cancer, the role of neoadjuvant chemotherapy (NACT) on the local immune microenvironment is largely unexplored. We performed a pilot study on 13 primary cervical tumor samples, before and after NACT, to phenotype and enumerate tumor-infiltrating T-cell subpopulations using multiplex immunohistochemistry (CD3, CD8, FoxP3, Ki67, and Tbet) and automated co-expression analysis software. A significant decrease in proliferating (Ki67+) CD3+CD8− T cells and FoxP3+(CD3+CD8−) regulatory T cells was observed in the tumor stroma after cisplatin and paclitaxel treatment, with increased rates of cytotoxic CD8+ T cells, including activated and CD8+Tbet+ T cells. No effect was observed on the number of tumor-infiltrating T cells in the cervical tumor microenvironment after treatment with cisplatin only. Therefore, we conclude that patients treated with cisplatin and paclitaxel had more tumor-infiltrating T-cell modulation than patients treated with cisplatin monotherapy. These findings enhance our understanding of the immune-modulating effect of chemotherapy and warrant future combination of the standard-of-care therapy with immunotherapy to improve clinical outcome in patients with cervical cancer.

/pdf/neoadjuvant-cisplatin-and-paclitaxel-modulate-tumor-2cfsv4qv6e.pdf

Neoadjuvant cisplatin and paclitaxel modulate tumor-infiltrating T cells in patients with cervical cancer.

// Shuaibin Liu 1 , Xiaoming Hao 1 , Xiaolan Ouyang 1 , Xiaojing Dong 1 , Yixuan Yang 2 , Tinghe Yu 1 , Jianguo Hu 1 , Lina Hu 1 1 Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China 2 Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China Correspondence to: Li-Na Hu, email: cqhulina@126.com Keywords: iTRAQ, cervical cancer, LYN, STAT3, IL-6 Received: March 28, 2016      Accepted: September 02, 2016      Published: September 26, 2016 ABSTRACT Cervical cancer is one of the most common malignant tumor in women. The mechanisms of cervical cancer are intricate and have not been fully understood. Therefore, we employed iTRAQ to obtain novel proteins profile which participates in the tumor oncogenesis of cervical cancer. 3300 proteins were identified aberrantly expressed in cervical cancer, and western bolt was performed to validate the results of iTRAQ. Then, we selected LYN for further study. Immunohistochemistry identified that LYN expression was significantly increased in cervical cancer tissues than that in cancer adjacent normal cervical tissues and normal cervical tissues. The increased LYN expression was significantly correlated with cancer differentiation and FIGO stage. Silencing LYN inhibited cell proliferation, migration and invasion, conversely, overexpression LYN promoted cell proliferation, migration and invasion. In terms of mechanism, LYN could also promote cervical cancer cells metastasis through activating IL-6/STAT3 pathway. In vivo study, overexpression LYN promoted tumor growth, meanwhile knockdown LYN inhibited tumor growth. These results indicate that LYN tyrosine kinase is an oncogenic gene and can serve as a novel target for cervical cancer research and therapy.

/pdf/tyrosine-kinase-lyn-is-an-oncotarget-in-human-cervical-1ptw6siny3.pdf

Tyrosine kinase LYN is an oncotarget in human cervical cancer: A quantitative proteomic based study

Programmed death-ligand 1 (PD-L1) has been reported to be expressed in many types of tumor cells, and bind to PD-1 on T lymphocytes to inhibit immune response. Immunologic checkpoint blockade with antibodies that target the PD1/PD-L1 pathway has demonstrated to have impressive antitumor effects on many malignancies. However, the significance of PD1/PD-L1 pathway in cervical cancer remains unclear. Here we studied PD-L1, PD-1, CD8 and HPV expression in cervical cancer and normal cervix by immunohistochemical staining. Our results showed that there was more frequently positive for PD-L1, PD-1 and CD8 in cervical cancer tissues compared to normal tissues, especially those strongly stained HPV. Additionally, PD-L1, PD-1 and CD8 were more frequently stained in tissues from advanced tumor and tumor with lymphoid nodes or vascular invasion respectively. Tissues from patients with chemotherapy history had over expression of PD-L1 in tumor cells and more PD-1 and CD8 in stromal mononuclear cells, which were identified as tumor infiltrated lymphocytes (TILs). These findings point to a key role of PD-L1 in immune escape of cervical cancer, and provide a rationale for therapeutic targeting of the PD-1/PD-L1 pathway.

PD-L1 Expression Correlates With Tumor Infiltrating Lymphocytes And Response To Neoadjuvant Chemotherapy In Cervical Cancer.

Cervical cancer is a prevalent and devastating malignancy in females worldwide. Nucleoporin 93 (Nup93), a member of the nuclear pore complex, plays an important role in transport across the nuclear pore. Several nucleoporins have been linked to cancer. However, the oncogenic role and underlying mechanism of Nup93 in cervical cancer development have not been reported. In this study, the expression of Nup93 was analyzed by quantitative real-time polymerase chain reaction (qPCR), western blot analysis, and immunohistochemical staining in cervical cancer tissues and cell lines. We found that the expression of Nup93 was higher in cervical cancer samples, compared to normal cervical samples. The knockdown of Nup93 inhibited cell proliferation, migration, and invasion capacity of cervical cancer cells. At the same time, we also found that silencing of Nup93 could inhibit cellular migration and invasion by regulating cytoskeleton actin and Rho family proteins. Nup93 also participated in the IL-6/STAT3 signaling pathway. In addition, down-regulation of Nup93 prevented tumor formation in mice in vivo. Thus, Nup93 may be a carcinogenic gene and serve as a potential therapeutic target for cervical cancer.

Expression of Nup93 is associated with the proliferation, migration and invasion capacity of cervical cancer cells.

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Tyrosine kinase LYN is an oncotarget in human cervical cancer: A quantitative proteomic based study

PD-L1 Expression Correlates With Tumor Infiltrating Lymphocytes And Response To Neoadjuvant Chemotherapy In Cervical Cancer.

Expression of Nup93 is associated with the proliferation, migration and invasion capacity of cervical cancer cells.