Tumor Inflammation, Obesity, and Proliferative Status as Biomarkers in Gastroesophageal Adenocarcinoma

Recent epidemiological studies have shown that obesity, typically measured by increased body mass index (BMI), is associated with an increased risk of gastroesophageal adenocarcinoma (GEAC), but the contributing molecular and immune mechanisms remain unknown. Since obesity is known to promote chronic inflammation, we hypothesized that obesity leads to inflammation-related immune dysfunction, which can be reversed by immune-modulating therapy. To test our hypothesis, we examined the clinical and molecular data from advanced GEAC patients. To this end, 46 GEAC tumors were evaluated for biomarkers representing tumor inflammation, cell proliferation, and PD-L1 expression. A CoxPH regression model with potential co-variates, followed by pairwise post hoc analysis, revealed that inflammation in the GEAC tumor microenvironment is associated with improved overall survival, regardless of BMI. We also observed a significant association between cell proliferation and progression-free survival in overweight individuals who received immune-modulating therapy. In conclusion, our data confirm the role of the immune system in the natural course of GEAC and its responses to immunotherapies, but do not support the role of BMI as an independent clinically relevant biomarker in this group of patients.

339 Immune profiling to investigate improved survival in patients with metastatic triple-negative breast cancer receiving trilaciclib prior to chemotherapy

BackgroundTrilaciclib is an intravenous cyclin-dependent kinase 4/6 inhibitor approved to reduce the incidence of chemotherapy-induced myelosuppression in patients with extensive-stage small cell lung cancer (myeloprotection). In a randomized, open-label phase 2 trial in patients with metastatic triple-negative breast cancer (mTNBC), adding trilaciclib prior to gemcitabine/carboplatin (GCb) increased overall survival in both PD-L1–positive and –negative populations versus GCb alone.1 2 We investigated potential immune mechanisms of anti-tumor efficacy among patients who received trilaciclib plus GCb.MethodsPeripheral blood was collected prior to and on treatment for flow cytometric analysis, and total RNA isolated from diagnostic tumor biopsies for sequencing. Differential gene expression analysis between responders and non-responders was based on negative binomial distribution and related pathways identified by Kyoto Encyclopedia of Genes and Genomes pathway analysis. Tumor inflammation signatures and deconvolution-based approaches were used to assess the tumor immune microenvironment. PD-L1 expression was considered positive if ≥1% of the total tumor area contained PD-L1–labelled immune cells (Ventana SP142 assay). Patients were defined as responders (confirmed complete or partial response) or non-responders (stable or progressive disease) according to RECIST criteria.ResultsOf 68 patients who received trilaciclib prior to GCb, tumor response status and RNA sequencing data were available for 51 patients, comprising 24 responders and 27 non-responders. Tumors from responders had 253 differentially expressed genes compared with non-responders. Analysis of immune gene signatures revealed a higher T-cell exhaustion score at baseline among responders versus non-responders (P=0.044).Among patients with PD-L1–positive tumors, responders had a greater peripheral immune response at baseline compared with non-responders, including more T cells (P=0.037; particularly memory CD8 T cells [P=0.042]), and a trend toward fewer myeloid-derived suppressor cells (MDSCs). Additionally, tumors from responders had more dendritic cells (P=0.044) and a trend toward enriched tumor inflammation signatures compared with non-responders.By contrast, among patients with PD-L1–negative tumors, responders had similar peripheral immune populations at baseline compared with PD-L1–negative non-responders, but fewer MDSCs (P=0.016), and a trend toward increased T-cell numbers after two cycles of trilaciclib plus GCb.Responders with both PD-L1–positive and –negative tumors had increased numbers of naïve CD8 T cells after two treatment cycles compared with non-responders.ConclusionsThe data suggest that adding trilaciclib prior to GCb enhances antitumor efficacy by modulating the composition of immune cell subsets. The impact of trilaciclib on changes to the tumor-infiltrating immune response is being further investigated in a phase 3 trial in patients with mTNBC (NCT04799249).AcknowledgementsFlow cytometry and RNA sequencing analyses were performed by Covance, Inc., and Q2 Laboratory Solutions, respectively.Trial Registration www.clinicaltrials.govNCT02978716ReferencesTan AR, Wright GS, Thummala AR, Danso MA, Popovic L, Pluard TJ, Han HS, Vojnović Ž, Vasev N, Ma L, Richards DA, Wilks ST, Milenković D, Yang Z, Antal JM, Morris SR, O’Shaughnessy J. Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol 2019;20(11):1587–1601.O’Shaughnessy J, Wright GS, Thummala AR, Danso MA, Popovic L, Pluard TJ, Han HS, Vojnović Ž, Vasev N, Ma L, Richards DA, Wilks ST, Milenković D, Xiao J, Sorrentino JA, Horton J, Tan AR. Abstract PD1-06: trilaciclib improves overall survival when given with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: final analysis of a randomized phase 2 trial. Cancer Res 2021;81(4 Supplement):PD1-06.Ethics ApprovalThe study protocol and all associated amendments and study-related materials were approved by the institutional review board or independent ethics committee of each investigational site.

The proteasome regulator PSME4 drives immune evasion and abrogates anti-tumor immunity in NSCLC

Protein degradation by proteasomes is important for the immune response against tumors. Antigens generated by the proteasome promote immune cell infiltration into tumors and improve tumor response to immunotherapy. For example, immunoproteasomes – a subset of proteasomes induced by inflammatory signals – may improve the response of melanomas to immune checkpoint inhibitors (ICI) by eliciting tumor inflammation. Yet, it is unclear whether and how protein degradation by proteasomes impacts cancer progression and contributes to immune evasion and resistance. Here, we profile the proteasome-cleaved peptides in lung cancers and find that PSME4 serves as a novel inhibitory regulator of the immunoproteasome, playing an anti-inflammatory role in cancer. Biochemical assays combined with scRNA-seq, immunopeptidomics and in vivo analyses demonstrate that PSME4 promotes an immunosuppressive environment around the tumor and abrogates anti-tumor immunity by inhibiting antigen presentation and attenuating tumor inflammation. Furthermore, we find that PSME4 expression is correlated with responsiveness to ICI across several cancer types. Our findings suggest that PSME4-mediated regulation of proteasome activity is a novel mechanism of immune evasion in non-small-cell lung carcinoma and may be targeted therapeutically for restoring anti-tumor immunity.

SERPINs in Macrophage May Be Key Inflammation Regulator and Relevant to Poor Prognosis in Adamantinomatous Craniopharyngioma

Craniopharyngioma is one of the most prevalent sellar tumors in children. Though normally, gross resection might be reached, while the prognosis and outcome of the patient is much more worse than any other benign tumor. Inflammation in tumor is of essential in tumor growth and progression. We found that inflammation was relevant to patient outcome and macrophages in adamantinomatous craniopharyngioma were activated in an interesting pattern. We then evaluated immune microenvironment in adamantinomatous craniopharyngioma and intended to screen out potential functional molecules for therapeutic targets and predicting prognosis. The results showed that SERPINs family, especially SERPINE1 and SERPING1 were up-regulated in adamantinomatous craniopharyngioma and might be related to patient outcome in malignant tumor. At the same time, the immune environment of adamantinomatous craniopharyngioma was similar with glioma rather than other benign brain tumors. The study firstly proposes the view that ACP might share the same characteristics with malignant brain tumor, and meanwhile preliminarily demonstrates SERPINs, especially SERPINE1 might also play a critical role in ACP, just like other aggressive cancer.

Second near-infrared (NIR-II) imaging: a novel diagnostic technique for brain diseases

Imaging in the second near-infrared II (NIR-II) window, a kind of biomedical imaging technology with characteristics of high sensitivity, high resolution, and real-time imaging, is commonly used in the diagnosis of brain diseases. Compared with the conventional visible light (400–750 nm) and NIR-I (750–900 nm) imaging, the NIR-II has a longer wavelength of 1000–1700 nm. Notably, the superiorities of NIR-II can minimize the light scattering and autofluorescence of biological tissue with the depth of brain tissue penetration up to 7.4 mm. Herein, we summarized the main principles of NIR-II in animal models of traumatic brain injury, cerebrovascular visualization, brain tumor, inflammation, and stroke. Simultaneously, we encapsulated the in vivo process of NIR-II probes and their in vivo and in vitro toxic effects. We further dissected its limitations and following optimization measures.

Tumour inflammation signature and expression of S100A12 and HLA class I improve survival in HPV-negative hypopharyngeal cancer

Hypopharyngeal squamous cell carcinoma (HPSCC) has a very poor prognosis. Local surgery may increase survival, but is often avoided due to significant post-op co-morbidities. Since prognostic markers are lacking, the aim was to find predictive biomarkers that identify patients whose response to oncological treatment is poor and who may benefit from primary surgery to increase survival. Pretreatment biopsies from 23 HPSCC patients, 3 human papillomavirus (HPV) positive and 20 HPV-negative, were analyzed for expression of 750 mRNAs using the Nanostring nCounter IO360 panel in relation to 3-year survival. Validation was performed through immunohistochemistry (IHC) for HLA class I and S100A12 in 74 HPV-negative HPSCC samples. Clustering identified a subset of HPV-negative HPSCC with favorable prognosis and a gene expression signature overexpressing calgranulins and immune genes, distinct from that of HPV-positive HPSCC. Enrichment analysis showed immune signaling, including the tumor inflammation signature, to be enriched in surviving patients. IHC validation confirmed high S100A12 and HLA class I expression to correlate with survival in HPV-negative HPSCC. This shows that immune activity is strongly related to survival in HPV-negative HPSCC. Enrichment of the tumor inflammation signature indicates a potential benefit of immunotherapy. Low expression of both HLA class I and S100A12 could be used to select patients for local surgery.