Purpose: Although tumor mutation burden (TMB) has been well known to predict the response to immune checkpoint inhibitors (ICI), lack of randomized clinical trial data has restricted its clinical application. This study aimed to explore the significance and feasibility of biomarker combination based on TMB and copy-number alteration (CNA) for the prognosis of each tumor and prediction for ICI therapy in metastatic pan-cancer milieu.Experimental Design: Non-ICI-treated MSK pan-cancer cohort was used for prognosis analysis. Three independent immunotherapy cohorts, including non-small cell lung cancer (n ¼ 240), skin cutaneous melanoma (n ¼ 174), and mixed cancer (Dana-Farber, n ¼ 98) patients from previous studies, were analyzed for efficacy of ICI therapy.Results: TMB and CNA showed optimized combination for the prognosis of most metastatic cancer types, and patients with TMB low CNA low showed better survival. In the predictive analysis, both TMB and CNA were independent predictive factors for ICI therapy. Remarkably, when TMB and CNA were jointly analyzed, those with TMB high CNA low showed favorable responses to ICI therapy. Meanwhile, TMB high CNA low as a new biomarker showed better prediction for ICI efficacy compared with either TMB-high or CNA-low alone. Furthermore, analysis of the non-ICI-treated MSK pan-cancer cohort supported that the joint stratification of TMB and CNA can be used to categorize tumors into distinct sensitivity to ICI therapy across pan-tumors.Conclusions: The combination of TMB and CNA can jointly stratify multiple metastatic tumors into groups with different prognosis and heterogeneous clinical responses to ICI treatment. Patients with TMB high CNA low cancer can be an optimal subgroup for ICI therapy.

Chemotherapy and radiotherapy predominantly improve the clinical outcomes of patients with human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC). Whether this superiority goes on when treated with immune checkpoint inhibitors is still unclear. This study sought to determine the predictive value and potential mechanisms of HPV status for the treatment of programmed cell death 1 (PD-1)/ligand 1(PD-L1) inhibitors. We conducted an integrated analysis of the relationships between HPV status and PD-L1, tumor mutation burden (TMB) and inflammation-related immune cells and molecules, based on the analysis of repository databases and resected HNSCC specimens. The pooled analysis of overall survival (OS) and objective response rate (ORR) suggested that HPV-positive patients benefited more from PD-1/PD-L1 inhibitors than HPV-negative patients (OS: hazard ratio (HR) = 0.71, p = 0.02; ORR: 21.9% vs 14.1%, odds ratio (OR) = 1.79, p = 0.01). Analysis of public databases and resected HNSCC specimens revealed that HPV status was independent of PD-L1 expression and TMB in HNSCC. However, HPV infection significantly increased T-cell infiltration, immune effector cell activation and the diversity of T-cell receptors. Notably, HPV-positivity correlated with increased immune cytolytic activity and a T-cell-inflamed gene expression profile. This work provides evidence that HPV status can be used to predict the effectiveness of PD-1 inhibitors in HNSCC, independently of PD-L1 expression and TMB, and probably results from an inflamed immune microenvironment induced by HPV infection.

BackgroundProtein kinase CK2 is a highly conserved, ubiquitous protein serine/threonine kinase that phosphorylates many substrates and has a global role in numerous biological and pathological processes. Overexpression of the protein kinase CK2α subunit (CK2α) has been associated with the malignant transformation of several tissues, with not nearly as much focus on the role of CK2α in colorectal cancer (CRC). The aims of this study are to investigate the function and regulatory mechanism of CK2α in CRC development.MethodsExpression levels of CK2α were analyzed in 144 patients (104 with CRC and 40 with colorectal adenoma) by immunohistochemistry. Proliferation, senescence, motility and invasion assays as well as immunofluorescence staining and western blots were performed to assess the effect of CK2α in CRC.ResultsThe immunohistochemical expression of nuclear CK2α was stronger in tumor tissues than in adenomas and normal colorectal tissues. Suppression of CK2α by small-interfering RNA or the CK2α activity inhibitor emodin inhibited proliferation of CRC cells, caused G0/G1 phase arrest, induced cell senescence, elevated the expression of p53/p21 and decreased the expression of C-myc. We also found that knockdown of CK2α suppressed cell motility and invasion. Significantly, CK2α inhibition resulted in β-catenin transactivation, decreased the expression levels of vimentin and the transcription factors snail1 and smad2/3, and increased the expression of E-cadherin, suggesting that CK2α regulates the epithelial-mesenchymal transition (EMT) process in cancer cells.ConclusionsOur results indicate that CK2α plays an essential role in the development of CRC, and inhibition of CK2α may serve as a promising therapeutic strategy for human CRC.

No abstract

No abstract

Here, we report a reversible photoacoustic (PA) probe, BDP-DOH, to image the localized redox state in vivo via monitoring the dynamic changes of the redox couple, superoxide anion (O 2•−

Microneedles (MNs) are micron-scale polymeric or metallic structures that offer distinct advantages for vaccines by efficiently targeting skin-resident immune cells, eliminating injection-associated pain, and improving patient compliance. These advantages, along with recent studies showing therapeutic benefits achieved using traditional intradermal injections in human cancer patients, suggest MN delivery might enhance cancer vaccines and immunotherapies. We recently developed a new class of polyelectrolyte multilayers based on the self-assembly of model peptide antigens and molecular toll-like receptor agonists (TLRa) into ultrathin, conformal coatings. Here, we reasoned that these immune polyelectrolyte multilayers (iPEMs) might be a useful platform for assembling cancer vaccine components on MN arrays for intradermal delivery from these substrates. Using conserved human melanoma antigens and a potent TLRa vaccine adjuvant, CpG, we show that iPEMs can be assembled on MNs in an automated fashion. These films, prepared with up to 128 layers, are approximately 200 nm thick but provide cancer vaccine cargo loading >225 μg/cm2. In cell culture, iPEM cargo released from MNs is internalized by primary dendritic cells, promotes activation of these cells, and expands T cells during coculture. In mice, application of iPEM-coated MNs results in the codelivery of tumor antigen and CpG through the skin, expanding tumor-specific T cells during initial MN applications and resulting in larger memory recall responses during a subsequent booster MN application. This study support MNs coated with PEMs built from tumor vaccine components as a well-defined, modular system for generating tumor-specific immune responses, enabling new approaches that can be explored in combination with checkpoint blockade or other combination cancer therapies.

No abstract