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Pembrolizumab, an anti-PD-1 antibody, has been approved as first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma ((R/M) HNSCC). However, only a minority of patients benefit from immunotherapy, which highlights the need to identify novel biomarkers to optimize treatment strategies. CD137+ T cells have been identified as tumour-specific T cells correlated with immunotherapy responses in several solid tumours. In this study, we investigated the role of circulating CD137+ T cells in (R/M) HNSCC patients undergoing pembrolizumab treatment. PBMCs obtained from 40 (R/M) HNSCC patients with a PD-L1 combined positive score (CPS) ≥1 were analysed at baseline via cytofluorimetry for the expression of CD137, and it was found that the percentage of CD3+CD137+ cells is correlated with the clinical benefit rate (CBR), PFS, and OS. The results show that levels of circulating CD137+ T cells are significantly higher in responder patients than in non-responders (p = 0.03). Moreover, patients with CD3+CD137+ percentage ≥1.65% had prolonged OS (p = 0.02) and PFS (p = 0.02). Multivariate analysis, on a combination of biological and clinical parameters, showed that high levels of CD3+CD137+ cells (≥1.65%) and performance status (PS) = 0 are independent prognostic factors of PFS (CD137+ T cells, p = 0.007; PS, p = 0.002) and OS (CD137+ T cells, p = 0.006; PS, p = 0.001). Our results suggest that levels of circulating CD137+ T cells could serve as biomarkers for predicting the response of (R/M) HNSCC patients to pembrolizumab treatment, thus contributing to the success of anti-cancer treatment.

Purpose: CD137 molecule is expressed by activated lymphocytes, and in patients with cancer identifies the tumor-reactive T cells. In solid tumors, high levels of circulating CD137+ T cells are associated with the clinical response and the disease-free status. Here, we examined the role of the CD137+ T cells in the improvement of patients' selection for immunotherapy treatment. Experimental Design: Peripheral blood mononuclear cells derived from 109 patients with metastatic cancer (66 patients for the identification cohort and 43 for the validation cohort) were analyzed for the expression of CD3, CD4, CD8, CD137, and PD1 molecules before the beginning of anti-PD1 therapy. Twenty healthy donors were used as control. The soluble form of CD137 (sCD137) was also analyzed. The CD137+ T cell subsets and the sCD137 were correlated with the clinicopathologic characteristics. The distribution of CD137+ T cells was also examined in different tumor settings. Results: The percentage of CD137+ T cells was higher in healthy donors and in those patients with a better clinical status (performance status = 0–1, n°metastasis≤2) and these high levels were ascribed to the CD8+CD137+ T cell population. The high frequency of CD137+ and CD8+CD137+ T cells resulted as a prognostic factor of overall survival (OS) and progression-free survival (PFS), respectively, and were confirmed in the validation cohort. High levels of CD3+CD137+PD1+ lymphocytes were associated with a low number of metastasis and longer survival. Instead, the high concentration of the immunosuppressive sCD137 in the serum is associated with a lower PFS and OS. In tumor bed, patients with a complete response showed a high percentage of CD137+ and CD8+ T cells. Conclusions: We propose the CD137+ T subset as an immune biomarker to define the wellness status of the immune system for successful anticancer immunotherapy.

Supplementary Table from Circulating CD137+ T Cells Correlate with Improved Response to Anti-PD1 Immunotherapy in Patients with Cancer

Supplementary Figure from Circulating CD137+ T Cells Correlate with Improved Response to Anti-PD1 Immunotherapy in Patients with Cancer

Purpose:CD137 molecule is expressed by activated lymphocytes, and in patients with cancer identifies the tumor-reactive T cells. In solid tumors, high levels of circulating CD137+ T cells are associated with the clinical response and the disease-free status. Here, we examined the role of the CD137+ T cells in the improvement of patients' selection for immunotherapy treatment.Experimental Design:Peripheral blood mononuclear cells derived from 109 patients with metastatic cancer (66 patients for the identification cohort and 43 for the validation cohort) were analyzed for the expression of CD3, CD4, CD8, CD137, and PD1 molecules before the beginning of anti-PD1 therapy. Twenty healthy donors were used as control. The soluble form of CD137 (sCD137) was also analyzed. The CD137+ T cell subsets and the sCD137 were correlated with the clinicopathologic characteristics. The distribution of CD137+ T cells was also examined in different tumor settings.Results:The percentage of CD137+ T cells was higher in healthy donors and in those patients with a better clinical status (performance status = 0–1, n°metastasis≤2) and these high levels were ascribed to the CD8+CD137+ T cell population. The high frequency of CD137+ and CD8+CD137+ T cells resulted as a prognostic factor of overall survival (OS) and progression-free survival (PFS), respectively, and were confirmed in the validation cohort. High levels of CD3+CD137+PD1+ lymphocytes were associated with a low number of metastasis and longer survival. Instead, the high concentration of the immunosuppressive sCD137 in the serum is associated with a lower PFS and OS. In tumor bed, patients with a complete response showed a high percentage of CD137+ and CD8+ T cells.Conclusions:We propose the CD137+ T subset as an immune biomarker to define the wellness status of the immune system for successful anticancer immunotherapy.

Purpose Single-agent immune checkpoint inhibitor (IO) therapy is the standard of care for non-oncogene addicted advanced non-small cell lung cancer (aNSCLC) with PD-L1 ≥ 50%. High tumor mutation burden (H-TMB) is a notable biomarker for IO response. Smoking-induced harm generates H-TMB in smoking aNSCLC patients (S-pts), whereas never-smoking patients (NS-pts) usually have low TMB and are IO-unresponsive. However, NS-pts with H-TMB have not been well molecularly characterized. Experimental design Clinical data of 142 aNSCLC patients with PD-L1 ≥ 50% treated with first-line pembrolizumab were retrospectively collected. Next-generation sequencing was performed using the FoundationOne®CDx assay to correlate genomic alterations with clinical characteristics and response outcomes. Detected mutations were classified into eleven main pathways: cell cycle, Hippo, Myc, Notch, oxidative stress/Nrf2, PI3K, RTK/RAS/MAP, TGF-b, p53, b-catenin/Wnt, and DDR. Enrichment analysis was performed on pathways with at least one mutation per patient to characterize patient subgroups based on mutated pathways. Moreover, to further investigate the molecular characterization of patients’ subgroups, we built and analyzed the patient similarity network exploiting the mutational profile to compute the pairwise similarity between patients. Results There were 111 S-pts and 31 NS-pts; S-pts had higher TMB (median TMB: 8 vs. 4 Mut/Mb). However, 11 NS-pts had high TMB (median TMB: 16.39 Mut/Mb) and were significantly enriched in b-catenin/Wnt and DDR pathway mutations (p-values=0.0027 and 0.0014, respectively) compared to others and H-TMB/S-pts. Using publicly available molecular characterization data (of 853 NSCLC patients from 2 randomized controlled trials), DDR pathway mutations were confirmed to be enriched in NS-pts with H-TMB. In the real world cohort the subgroup of H-TMB/NS-pts with DDR pathway mutation showed better IO response and survival. Moreover, the similarity network analysis of the NS-pts revealed the presence of one subgroup characterized by high TMB, improved OS and a prevalence of DDR pathway mutations. Conclusions DDR signature has a potential role as additional generator of H-TMB in NS-pts. This subgroup of IO-responsive NS-pts may have better prognosis.

Despite diagnostic and therapeutic improvements, glioblastoma (GB) remains one of the most threatening brain tumor in adults, underlining the urgent need of new therapeutic targets. Lectins are glycan-binding proteins that regulate several biological processes through the recognition of specific sugar motifs. Lectins and their ligands are found on immune cells, endothelial cells and, also, tumor cells, pointing out a strong correlation among immunity, tumor microenvironment and vascularization. In GB, altered glycans and lectins contribute to tumor progression and immune evasion, shaping the tumor-immune landscape promoting immunosuppressive cell subsets, such as myeloid-derived suppressor cells (MDSCs) and M2-macrophages, and affecting immunoeffector populations, such as CD8+ T cells and dendritic cells (DCs). Here, we discuss the latest knowledge on the immune cells, immune related lectin receptors (C-type lectins, Siglecs, galectins) and changes in glycosylation that are involved in immunosuppressive mechanisms in GB, highlighting their interest as possible novel therapeutical targets.

Blocking the Programmed Cell Death Protein 1 (PD-1)/programmed death ligand-1 (PD-L1) axis has demonstrated great efficacy in cancer immunotherapy treatment and remains the central modality of immune targeting. To support the rational and tailored use of these drugs, it is important to identify reliable biomarkers related to survival. The role of the soluble form of the PD-L1 (sPD-L1) as a prognostic biomarker related to survival in solid cancer patients treated with immunotherapy has not yet been consistently evaluated. A systematic literature search of original articles in PubMed, MEDLINE and Scopus was conducted. Studies reporting hazard ratios (HRs) with a 95% confidence interval (CI) or Kaplan–Meier curves or individual patient data for overall survival (OS) or progression-free survival (PFS) associated with baseline levels of sPD-L1 in cancer patients undergoing immunotherapy treatment were considered eligible. Twelve studies involving 1076 patients and different tumor types treated with immunotherapy were included in the analysis. High blood levels of sPD-L1 correlated with poorer OS and PFS in cancer patients treated with immunotherapy (HR = 1.49, 95%CI: 1.15, 1.93, p < 0.01, I2 = 77% for OS; HR = 1.59, 95%CI: 1.20, 2.12, p < 0.01, I2 = 82% for PFS). A subgroup analysis highlighted that high levels of sPD-L1 were associated with worse survival in patients affected by NSCLC (HR = 1.81 95%CI: 1.09–3.00, p = 0.02, I2 = 83% for OS; HR = 2.18, 95%CI: 1.27–3.76, p < 0.01, I2 = 88% for PFS). An HR > 1 indicated that patients with low levels of sPD-L1 have the highest rates of OS/PFS. In this meta-analysis, we clarified the role of sPD-L1 in different solid cancers treated exclusively with Immune checkpoint inhibitors (ICIs). sPD-L1 could represent a non-invasive biomarker that is easily dosable in the blood of patients. The pooled data from the selected studies showed that a high circulating concentration of sPD-L1 in cancer patients correlates with worse survival, suggesting that it may be a helpful prognostic biomarker for the selection of cancer patients before immunotherapy, thus improving the efficacy of ICIs and avoiding unnecessary treatment.

Unresectable recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) has a very poor prognosis. Soluble immune checkpoints (sICs) are circulating proteins that result from the alternative splicing of membrane proteins and can modulate the immune response to cancer cells. The aim of our pilot study was to determine the possible role of a comprehensive evaluation of sICs in the classification of prognosis and response to treatment in patients with advanced disease. We evaluated several sICs (CD137, CTLA-4, PD-1, PD-L1, PD-L2, TIM3, LAG3, GITR, HVEM, BTLA, IDO, CD80, CD27, and CD28) from peripheral blood at baseline and investigated the association with clinical characteristics and outcomes. A high baseline soluble LAG3 (sLAG3 &gt, 377 pg/mL) resulted in an association with poor PFS and OS (p = 0.047 and p = 0.003, respectively). Moreover, sLAG3 emerged as an independent prognostic factor using an MVA (p = 0.005). The evaluation of sICs, in particular sLAG3, may be relevant for identifying patients with worse prognoses, or resistance to treatments, and may lead to the development of novel targeted strategies.

Cabozantinib (XL-184) is a multitarget tyrosine kinase inhibitor (TKI) targeting receptor tyrosine kinases (RTKs) involved in oncogenesis and angiogenesis. It is currently the standard therapy for medullary thyroid cancer (MTC), metastatic renal cell carcinoma (mRCC), and hepatocellular carcinoma (HCC). Combination of Cabozantinib with immunotherapy is now a standard treatment in metastatic renal cancer, and its efficacy is being tested in ongoing clinical trial in prostate cancer patients. Here, we report that Cabozantinib may exert an immunostimulatory role by inducing immunogenic stress of prostate cancer cells and directly modulating dendritic cells (DCs). Cabozantinib treatment arrested the cell cycle and triggered immunogenic cell death (ICD) in prostate cancer cells in vitro. Cabozantinib had a direct effect on DCs by the down-modulation of β-catenin and change in migratory and costimulatory phenotype of the DCs. These results may suggest possible immunomodulatory effects induced by Cabozantinib that could be exploited to optimize patient-tailored immunotherapeutic treatments.

Patients with non-small cell lung cancer (NSCLC) have been shown to benefit from the introduction of anti-PD1 treatment. However, not all patients experience tumor regression and durable response. The identification of a string of markers that are direct or indirect indicators of the immune system fitness is needed to choose optimal therapeutic schedules in the management of NSCLC patients. We analyzed 34 immuno-related molecules (14 soluble immune checkpoints, 17 cytokines/chemokines, 3 adhesion molecules) released in the serum of 22 NSCLC patients under Nivolumab treatment and the gut metabolomic profile at baseline. These parameters were correlated with performance status (PS) and/or response to treatment. Nivolumab affected the release of soluble immune checkpoints (sICs). Patients with a better clinical outcome and with an optimal PS (PS = 0) showed a decreased level of PD1 and maintained low levels of several sICs at first clinical evaluation. Low levels of PDL1, PDL2, Tim3, CD137 and BTLA4 were also correlated with a long response to treatment. Moreover, responding patients showed a high proportion of eubiosis-associated gut metabolites. In this exploratory study, we propose a combination of immunological and clinical parameters (sICs, PS and gut metabolites) for the identification of patients more suitable for Nivolumab treatment. This string of parameters validated in a network analysis on a larger cohort of patients could help oncologists to improve their decision-making in an NSCLC setting.

Although migration-related detention has proliferated around the world, little is known about life inside these sites of confinement for illegalized non-citizens. Building on 34 months of fieldwork, this article examines the lived experiences of center staff and external civil-society actors engaged within Rome’s detention center. We discuss the emotional, ethical, and political challenges faced by these professional actors in their everyday work and their relationship with detainees. Our aim is to shed light on psychosocial life in detention and the intersections between humanitarian and security logics in this setting. In doing so, we problematize the idea that “humanizing detention” can be a solution for change. Fundação para a Ciência e Tecnologia - FCT info:eu-repo/semantics/acceptedVersion

Drawing on two years of fieldwork, this article focuses on the lived experiences of women detained inside Rome’s Identification and Expulsion Center, the main migration-related detention facility in Italy. We employed a thematic narrative analysis to examine the narratives of five women with different life trajectories in order to identify continuities and discontinuities within and across their stories. This analysis reveals that women’s experiences of oppression and agency—in their countries of origin, transit, and settlement—are deeply intertwined and strongly influenced by structural forces. Gender and sexuality, in relation to other hierarchies of power such as class, race, and nationality, profoundly shape such experiences, becoming crucial in the production of women as excludable and deportable subjects. Further, as the accounts of our participants lay bare, the immigration control system appears to play a key role in the (re)production of a dominant normative order. However, women are not passive spectators of the violence to which they are forcibly exposed. Rather, they struggle to cope with and resist the regimes of power that oppress their everyday lives. Through a feminist stance, this contribution seeks to enrich the body of scholarship on the lived experiences of women subject to practices of immigration and border control, particularly those confined in detention centers. Moreover, it highlights the need for a feminist project based on the creation of political and affective alliances across borders and axes of difference, particularly those related to legally produced statuses. Fundação para a Ciência e a Tecnologia - FCT info:eu-repo/semantics/publishedVersion

Pain is among the most frequent and distressing symptoms in terminally-ill cancer and, to date, many patients still experience uncontrolled pain. In this paper we evaluated prevalence and intensity of pain on admission in our palliative care center and during the first three days of care.From September 2009 to October 2009 we consecutively recruited 96 terminally-ill cancer patients : on admission more than 50% had severe pain and only 4% referred to be pain-free. 54% of patients was on treatment with strong opioids.After three days from admission in our palliative care unit only 7% of patients experienced severe pain, 25% reported absence of pain and 80% of patients was on treatment with strong opioids.The beginning of palliative care led to a meaningful and rapid reduction of pain in the vast majority of terminally-ill cancer patients evaluated in this study.

Pain is a distressing symptom in terminally-ill cancer and, to date, many patients still experience uncontrolled pain. We evaluated prevalence and intensity of pain at admission in Palliative Care Center. We recruited 323 patients: more than 80% referred moderate/severe pain and only 50% was adsuming strong opioids.