IFNγ-induced PD-L1 expression is JAK2 but not JAK1 dependent and its inhibition enhances NK-cetuximab mediated ADCC of HNSCC cells

Programmed death ligand 1 (PD-L1) is an immunosuppressive molecule expressed by many cancer types, including a large proportion of head and neck cancers (HNC), and ligation of its receptor, programmed death 1 (PD-1), induces exhaustion of effector T cells. It has been shown that interferon gamma (IFNγ) induces PD-L1 expression in many cancer types including glioblastoma, melanoma, lung and kidney cancer. Importantly, the stimuli and mechanism for PD-L1 upregulation in HNC cells are not well characterized. IFNγ signals through Janus Kinase 1/2 (JAK1/2) heterodimer complex and mediates signal transducer and activator of transcription 1 (STAT1) phosphorylation, leading to type I cytokine expression, upregulation of antigen presentation, and tumor cell recognition by cytolytic T lymphocytes (CTL). We investigated basal PD-L1 expression and the mechanism by which IFNγ signaling upregulates PD-L1 in HNC cells including dependence on JAK/STAT pathway. We observed that IFNγ signaling increased PD-L1 expression in a JAK2 but not JAK1 dependent fashion. In addition, interferon alpha (IFNα), which signals via JAK1/TYK2 did not upregulate PD-L1 expression while still upregulated HLA class I. Specific JAK2 inhibition downregulated NK cell-derived IFNγ induced PD-L1 expression and enhanced cetuximab mediated ADCC. Our data suggest a crucial role for JAK2/STAT1 in IFNγ mediated PD-L1 upregulation. JAK2 inhibition provides a promising strategy to increase tumor cell lysis through maintaining HLA class I while suppressing tumor cell expressed PD-L1 in combination with anti-EGFR cetuximab therapy

Epidermal growth factor receptor and Janus Kinase 2 regulation of programmed death ligand 1 and immunoescape in head and neck cancer

Co-inhibitory immune checkpoint receptors (ICR) are novel targets for cancer immunotherapy. Programmed death ligand 1 (PD-L1), expressed in many cancers, including head and neck cancers (HNC), interacts with its receptor, programmed death 1 (PD-1), resulting in an exhausted phenotype. As yet, the stimuli and pathways that induce PD-L1 expression in tumor cells are not fully understood. Interferon gamma (IFNγ) and the epidermal growth factor receptor (EGFR) utilize Janus kinase 2 (JAK2) as a common signaling node transmitting tumor cell-mediated extrinsic or intrinsic signals, respectively. We investigated the mechanisms by which these factors upregulate PD-L1 and immunosuppressive cytokine expression in HNC cells in the context of EGFR/JAK/STAT pathway activation. We found that wild type overexpressed EGFR significantly correlated with JAK2 and PD-L1 expression. Furthermore, PD-L1 expression was induced in an EGFR- and JAK2-dependent manner, and specific JAK2 inhibition prevented PD-L1 upregulation in HNC, enhancing their immunogenicity. HNC tumors have higher expression of immunosuppressive cytokines including TGFβ, IL-10, VEGF-A and IDO and lower expression of inflammatory cytokines such as IL-12A and IL-17A than controls. EGFR/JAK2 inhibition downregulated secretion of these STAT3-dependent cytokines in vitro, suggesting that targeting the EGFR/JAK2/STAT3 suppressive pathway may reverse tumor immunoescape. This view is supported by in vivo findings where HNC patients unresponsive to cetuximab therapy had significantly higher concentrations of immunosuppressive cytokines. NK cells are crucial for promoting T cell responses against cancer. However, NK cell PD-1 expression remains largely undefined. Cetuximab-activated NK cells constitute the major effector cell subset that lyses tumor targets via antibody dependent cellular cytotoxicity (ADCC). We demonstrate that expression of PD-1 in HNC tumors correlates with NK cell activation markers. HNC patients exhibit higher levels of circulating PD-1+ NK cells, which are further enriched in the tumor. Interestingly, cetuximab treatment increased this frequency in vitro and in vivo. Inhibition of the PD-L1/PD-1 axis increased cetuximab-mediated NK cell activation and cytotoxicity. Collectively, our findings suggest a novel role for JAK2 in EGFR-mediated PD-L1 upregulation and immunosuppressive cytokine secretion. Importantly, combined inhibition of the EGFR and PD-L1/PD-1 axis presents a potential strategy to reverse cetuximab-resistant immune evasion of HNC by enhancing NK cell cytotoxicity

Reversing EGFR Mediated Immunoescape by Targeted Monoclonal Antibody Therapy

Uncontrolled growth is a signature of carcinogenesis, in part mediated by overexpression or overstimulation of growth factor receptors. The epidermal growth factor receptor (EGFR) mediates activation of multiple oncogenic signaling pathways and escape from recognition by the host immune system. We discuss how EGFR signaling downregulates tumor antigen presentation, upregulates suppressive checkpoint receptor ligand programmed death ligand (PD-L1), induces secretion of inhibitory molecules such as transforming growth factor beta (TGFβ) and reprograms the metabolic pathways in cancer cells to upregulate aerobic glycolysis and lactate secretion that ultimately lead to impaired cellular immunity mediated by natural killer (NK) cell and cytotoxic T lymphocytes (CTL). Ultimately, our understanding of EGFR-mediated escape mechanisms has led us to design EGFR-specific monoclonal antibody therapies that not only inhibit tumor cell metabolic changes and intrinsic oncogenic signaling but also activates immune cells that mediate tumor clearance. Importantly, targeted immunotherapy may also benefit from combination with antibodies that target other immunosuppressive pathways such PD-L1 or TGFβ and ultimately enhance clinical efficacy

Coronavirus pandemic: An opportunity to study the anthropogenic impact on micro-climate conditions and CaCO3 crystal morphology in the Nerja Cave (SE Spain)

Funding charge open access: University of Malaga / CBUA. It is financed by the Nerja Cave Foundation, co-ordinated by its Research Institute and authorized by the Consejería de Cultura (Junta de Andalucía). This study is also a contribution to the Research Groups RNM-308 and RNM-126 of the Junta de Andalucía and to the Projects PID2021-125619OB-C21, PID2021-125619OB-C22, TED2021-130549B-I00 funded by MCIN/AEI/10.13039/501100011033.Following the declaration of the COVID-19 pandemic, the Spanish Government restricted non-essential movements of all citizens and closed all public spaces, such as the Nerja Cave, until May 31, 2020. This particular condition of the closure of the cave provided a unique opportunity to study the micro-climate conditions and carbonate precipitation in this tourist cave without the presence of visitors. Our results show the significant effect of visitors on the air isotopic signature of the cave and on the genesis of the extensive dissolution features affecting the carbonate crystals formed in the tourist sector of the cave, alerting us to the possible corrosion of the speleothems located there. The movement of visitors within the cave also favours the mobilisation of aerial fungi and bacterial spores and their subsequent sedimentation simultaneously with the abiotic precipitation of carbonates from the drip water. The traces of these biotic elements could be the origin of the micro-perforations previously described in the carbonate crystals formed in the tourist galleries of the cave, but they are subsequently enlarged due to abiotic dissolution of the carbonates through these weaker zones.University of MalagaNerja Cave FoundationJunta de Andalucia RNM-308, RNM-126PID2021-125619OB-C21, PID2021-125619OB-C22, TED2021-130549B-I00, MCIN/AEI/10.13039/50110001103

EGFR-mediated tumor immunoescape: The imbalance between phosphorylated STAT1 and phosphorylated STAT3

The epidermal growth factor receptor (EGFR) supports the escape of malignant cells from immunosurveillance by inhibiting the activation of signal transducer and activator of transcription 1 (STAT1) while promoting that of STAT3. We have recently demonstrated that protein tyrosine phosphatase, non-receptor type 11 (PTNP11, best known as SHP2), a phosphatase that operates downstream of EGFR, is responsible for the dephosphorylation of active STAT1 and for the inhibition of the antigen-processing machinery (APM), hence favoring tumor immunoescape. Thus, EGFR signaling may skew the tumor microenvironment to suppress cellular immune responses

PD-1 is a marker of activation on tumor infiltrating NK cells in head and neck cancer

Co-inhibitory immune checkpoint receptors have become important targets for cancer immunotherapy. Programmed death 1 (PD-1) has been well-characterized on T cells in many cancer types, including head and neck cancer (HNC), for its ability to mediate activation and eventually T cell exhaustion in the tumor microenvironment. However, PD-1 expression on NK cells, which are crucial innate immune effector cells against cancer, remains largely undefined. In the setting of HNC, NK cells mediate lysis of EGFR-overexpressing tumor targets via cetuximab-mediated antibody dependent cytotoxicity (ADCC). Indeed, cetuximab has shown to be clinically effective but only to a modest extent. Therefore, it is necessary to investigate how cetuximab modulates activation of immune effector cell infiltrates in the tumor microenvironment in order to improve or extend its therapeutic efficacy. We hypothesized that expression of PD-1 per se on NK cells may constitute a marker of a chronically activated phenotype, which is suppressed only after ligation by its cognate ligand programmed death ligand-1 (PD-L1). Thus, tumor cell-expressing PD-L1 may present as a crucial mediator of immunosuppression in the tumor microenvironment decreasing cytotoxicity of cetuximab activated PD-1 expressing NK cells. Herein, using The Cancer Genome Atlas (TCGA) data for 500 HNC patients' tumors, we found that PD-1 expression correlates with NK activation markers. Indeed, HNC patients also exhibit higher levels of circulating and tumor infiltrating PD-1+ NK cells, and neoadjuvant cetuximab treatment increased this frequency in vitro and in vivo in a prospective Phase II trial. In addition, anti-PD-1 mAb nivolumab enhanced cetuximab mediated NK cell activation and HNC cell lysis. Therefore, blocking PD-L1/PD-1 axis may be a useful approach to reverse immune evasion of HNC tumors to cetuximab therapy by reversing NK cell dysfunction

Anti-EGFR targeted monoclonal antibody isotype influences anti-tumor immunity in head and neck cancer patients

EGFR is frequently overexpressed on several cancers, and two targeted antibodies are FDA approved but differ by isotype. Cetuximab (IgG1 isotype) has been shown to be effective at both inhibiting downstream signaling of EGFR and activating anti-tumor, cellular immune mechanisms. While panitumumab (IgG2 isotype) can inhibit downstream EGFR signaling similar to cetuximab, panitumumab might also induce antibody-dependent cell cytotoxicity (ADCC) or adaptive immunity. We sought to investigate the cellular immunity specifically activated by cetuximab or panitumumab showing that both mAb primarily activate NK cells, although cetuximab was significantly more potent than panitumumab. We also observed that although panitumumab may activate monocytes through the CD32 (FcγRIIa) receptor, neither mAb activated monocytes sufficiently to mediate ADCC. Cetuximab enhanced DC maturation to a greater extent than panitumumab, corresponding with improved cross presentation of tumor antigen by cetuximab compared with panitumumab. Indeed, improved adaptive immune responses with increased EGFR-specific cytotoxic CD8+ T cells were present in patients treated with cetuximab compared to those treated with panitumumab. These results suggest that although panitumumab effectively inhibits EGFR signaling to a similar extent as cetuximab, it is less effective at mediating anti-tumor, cellular immune mechanisms which may be crucial for effective therapy for HNSCC

Immunotherapy of head and neck cancer: Emerging clinical trials from a National Cancer Institute Head and Neck Cancer Steering Committee Planning Meeting.

Recent advances have permitted successful therapeutic targeting of the immune system in head and neck squamous cell carcinoma (HNSCC). These new immunotherapeutic targets and agents are being rapidly adopted by the oncologic community and hold considerable promise. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issue of how to further investigate the use of immunotherapy in patients with HNSCC. The goals of the meeting were to consider phase 2 or 3 trial designs primarily in 3 different patient populations: those with previously untreated, human papillomavirus-initiated oropharyngeal cancers; those with previously untreated, human papillomavirus-negative HNSCC; and those with recurrent/metastatic HNSCC. In addition, a separate committee was formed to develop integrative biomarkers for the clinical trials. The meeting started with an overview of key immune components and principles related to HNSCC, including immunosurveillance and immune escape. Four clinical trial concepts were developed at the meeting integrating different immunotherapies with existing standards of care. These designs were presented for implementation by the head and neck committees of the National Cancer Institute-funded National Clinical Trials Network. This article summarizes the proceedings of this Clinical Trials Planning Meeting, the purpose of which was to facilitate the rigorous development and design of randomized phase 2 and 3 immunotherapeutic trials in patients with HNSCC. Although reviews usually are published immediately after the meeting is held, this report is unique because there are now tangible clinical trial designs that have been funded and put into practice and the studies are being activated to accrual. Cancer 2017;123:1259-1271. © 2016 American Cancer Society

Evidencias de paleosismos en la estratigrafía de la cuenca cuaternaria Cusco

El Perú se encuentra en el borde occidental del continente sudamericano, donde la Cordillera de los Andes se hace más ancha y alta. Esta cadena montañosa se ubica sobre el límite de placas convergentes en el cual la placa oceánica de Nazca subduce la placa Sudamericana o Continental. El borde occidental de América del Sur se caracteriza por ser una de las zonas sísmicamente más activas en el mundo, donde la sismicidad está asociada al proceso de subducción y a las reactivaciones de fallas. En el Perú, se ha avanzado hasta el punto de haber identificado, cartografiado y reconocido las características de los sistemas de fallas activas mayores del país. Uno de los sistemas de fallas más importantes del Perú se encuentra en la Cordillera Oriental, exactamente en el departamento del Cusco, ubicado en el sur del Perú (Fig. 1 ). La información sobre sismos en el Cusco es insuficiente para realizar trabajos sobre peligro sísmico. Crónicas históricas (Esquivel & Navia, 1775; Silgado, 1978) mencionan la ocurrencia de sismos muy devastadores para la ciudad del Cusco, estas remontándose hasta la época Inca. La falta de datos y limitaciones de la sismicidad histórica nos conduce a realizar trabajos de paleosismología, que permitirán identificar las estructuras geológicas asociadas a sismos ocurridos antes de las primeras crónicas históricas, mediante un análisis integral de disciplinas como son: La Geología Estructural, Estratigrafía y Sedimentología. La paleosismología estudia la estructura sísmica directa (la falla) realizando una trinchera o zanja siempre y cuando ocurra ruptura superficial durante el sismo, pero esto no siempre es así, ya que se pueden dar terremotos muy importantes sin rupturas superficiales. Por este motivo el estudio de las estructuras de origen sísmico desarrollado en sedimentos no consolidados cobra especial importancia, siendo el tema central del presente trabajo

Nivolumab treatment beyond RECIST-defined progression in recurrent or metastatic squamous cell carcinoma of the head and neck in CheckMate 141: A subgroup analysis of a randomized phase 3 clinical trial

BACKGROUND: Response patterns with immune checkpoint inhibitors may be different from those with chemotherapy. Therefore, assessment of response to immunotherapy with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, could result in premature treatment termination. The randomized, open-label, phase 3 CheckMate 141 trial (NCT02105636), which evaluated nivolumab in recurrent/metastatic squamous cell carcinoma of the head and neck after platinum therapy, allowed treatment beyond first RECIST-defined progression (TBP) according to protocol-specified criteria. METHODS: In CheckMate 141, patients with RECIST-defined progression who had a stable performance status and demonstrated clinical benefit without rapid disease progression were permitted to receive TBP with nivolumab at 3 mg/kg every 2 weeks until further progression, which was defined as an additional 6510% increase in tumor volume. This post hoc analysis evaluated outcomes for patients who received TBP with nivolumab. RESULTS: Of 240 patients randomized to nivolumab, 146 experienced RECIST-defined progression. Sixty-two of these patients received TBP, and 84 discontinued treatment (no TBP). Among the 60 TBP patients evaluable for response, 15 (25%) had no change in their tumor burden, and 15 (25%) had reductions in target lesion size; 3 patients (5%) had reductions >30%. The median overall survival among TBP patients was 12.7 months (95% confidence interval, 9.7-14.6 months). No new safety signals were observed with TBP. Exploratory analyses of immune cell biomarkers suggested a potential relationship with initial and TBP responses. CONCLUSIONS: Tumor burden reduction was noted in a proportion of patients who received TBP with nivolumab in CheckMate 141. Additional research is warranted to identify factors predictive of a TBP benefit in this population