A long non-coding RNA links calreticulin-mediated immunogenic cell removal to RB1 transcription

A subset of promoters bidirectionally expresses long non-coding RNAs (ncRNAs) of unknown function and protein-coding genes (PCGs) in parallel. Here, we define a set of 1107 highly conserved human bidirectional promoters that mediate the linked expression of long ncRNAs and PCGs. Depletion of the long ncRNA expressed from the RB1 promoter, ncRNA-RB1, reveals regulatory effects different from the RB1-controlled transcriptional program. ncRNA-RB1 positively regulates the expression of calreticulin (CALR) that in response to certain therapeutic interventions can translocate from the endoplasmic reticulum to the cell surface, hence activating anticancer immune responses. Knockdown of ncRNA-RB1 in tumor cells reduced expression of CALR, impaired the translocation of the protein to the cell surface upon treatment with anthracylines and consequently inhibited the cellular uptake by macrophages. In conclusion, co-transcription of ncRNA-RB1 and RB1 provides a positive link between the expression of the two tumor suppressors RB1 and the immune-relevant CALR protein. This regulatory interplay exemplifies disease-relevant co-regulation of two distinct gene products, in which loss of expression of one oncosuppressor protein entails the abolition of additional tumor-inhibitory mechanisms

Mutually exclusive lymphangiogenesis or perineural infiltration in human skin squamous-cell carcinoma.

Although tumor-associated lymphangiogenesis correlates with metastasis and poor prognosis in several cancers, it also supports T cell infiltration into the tumor and predicts favorable outcome to immunotherapy. The role of lymphatic vessels in skin squamous-cell carcinoma (sSCC), the second most common form of skin cancer, remains mostly unknown. Although anti-PD-1 therapy is beneficial for some patients with advanced sSCC, a greater understanding of disease mechanisms is still needed to develop better therapies. Using quantitative multiplex immunohistochemistry, we analyzed sSCC sections from 36 patients. CD8+ T cell infiltration showed great differences between patients, whereby these cells were mainly excluded from the tumor mass. Similar to our data in melanoma, sSCC with high density of lymphatic endothelial cells showed increased CD8+ T cell density in tumor areas. An entirely new observation is that sSCC with perineural infiltration but without metastasis was characterized by low lymphatic endothelial cell density. Since both, metastasis and perineural infiltration are known to affect tumor progression and patients' prognosis, it is important to identify the molecular drivers, opening future options for therapeutic targeting. Our data suggest that the mechanisms underlying perineural infiltration may be linked with the biology of lymphatic vessels and thus stroma

Long-term benefit of lurbinectedin as palliative chemotherapy in progressive malignant pleural mesothelioma (MPM): final efficacy and translational data of the SAKK 17/16 study.

BACKGROUND The SAKK 17/16 study showed promising efficacy data with lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma. Here, we evaluated long-term outcome and analyzed the impact of lurbinectedin monotherapy on the tumor microenvironment at the cellular and molecular level to predict outcomes. MATERIAL AND METHODS Forty-two patients were treated with lurbinectedin in this single-arm study. Twenty-nine samples were available at baseline, and seven additional matched samples at day one of cycle two of treatment. Survival curves and rates between groups were compared using the log-rank test and Kaplan-Meier method. Statistical significance was set at P value <0.05. RESULTS Updated median overall survival (OS) was slightly increased to 11.5 months [95% confidence interval (CI) 8.8-13.8 months]. Thirty-six patients (85%) had died. The OS rate at 12 and 18 months was 47% (95% CI 32.1% to 61.6%) and 31% (95% CI 17.8% to 45.0%), respectively. Median progression-free survival was 4.1 months (95% CI 2.6-5.5 months). No new safety signals were observed. Patients with lower frequencies of regulatory T cells, as well as lower tumor-associated macrophages (TAMs) at baseline, had a better OS. Comparing matched biopsies, a decrease of M2 macrophages was observed in five out of seven patients after exposure to lurbinectedin, and two out of four patients showed increased CD8+ T-cell infiltrates in tumor. DISCUSSION Lurbinectedin continues to be active in patients with progressing malignant pleural mesothelioma. According to our very small sample size, we hypothesize that baseline TAMs and regulatory T cells are associated with survival. Lurbinectedin seems to inhibit conversion of TAMs to M2 phenotype in humans

The immunopeptidome landscape associated with T cell infiltration, inflammation and immune editing in lung cancer.

One key barrier to improving efficacy of personalized cancer immunotherapies that are dependent on the tumor antigenic landscape remains patient stratification. Although patients with CD3 &lt;sup&gt;+&lt;/sup&gt; CD8 &lt;sup&gt;+&lt;/sup&gt; T cell-inflamed tumors typically show better response to immune checkpoint inhibitors, it is still unknown whether the immunopeptidome repertoire presented in highly inflamed and noninflamed tumors is substantially different. We surveyed 61 tumor regions and adjacent nonmalignant lung tissues from 8 patients with lung cancer and performed deep antigen discovery combining immunopeptidomics, genomics, bulk and spatial transcriptomics, and explored the heterogeneous expression and presentation of tumor (neo)antigens. In the present study, we associated diverse immune cell populations with the immunopeptidome and found a relatively higher frequency of predicted neoantigens located within HLA-I presentation hotspots in CD3 &lt;sup&gt;+&lt;/sup&gt; CD8 &lt;sup&gt;+&lt;/sup&gt; T cell-excluded tumors. We associated such neoantigens with immune recognition, supporting their involvement in immune editing. This could have implications for the choice of combination therapies tailored to the patient's mutanome and immune microenvironment