Preclinical data and design of a phase I clinical trial of neoantigen-reactive TILs for advanced epithelial or ICB-resistant solid cancers.

Background: Adoptive cell therapy (ACT) of expanded tumor-infiltrating lymphocytes (TILs) can mediate objective tumor regression in 28%-49% of metastatic melanoma patients. However, the efficacy of TIL therapy in most epithelial cancers remains limited. We present the design of a phase I clinical study that aims to assess the safety and efficacy of NEXTGEN-TIL, a TIL product selected based on neoantigen recognition, in patients with advanced epithelial tumors and immune checkpoint blockade (ICB)-resistant solid tumors.

The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2.

Chemotherapy often generates intratumoral senescent cancer cells that strongly modify the tumor microenvironment, favoring immunosuppression and tumor growth. We discovered, through an unbiased proteomics screen, that the immune checkpoint inhibitor programmed cell death 1 ligand 2 (PD-L2) is highly upregulated upon induction of senescence in different types of cancer cells. PD-L2 is not required for cells to undergo senescence, but it is critical for senescent cells to evade the immune system and persist intratumorally.

Exploring the Immunogenicity of Noncanonical HLA-I Tumor Ligands Identified through Proteogenomics.

Purpose: Tumor antigens are central to antitumor immunity. Recent evidence suggests that peptides from noncanonical (nonC) aberrantly translated proteins can be presented on HLA-I by tumor cells. Here, we investigated the immunogenicity of nonC tumor HLA-I ligands (nonC-TL) to better understand their contribution to cancer immunosurveillance and their therapeutic applicability.

Cellular Senescence Is Immunogenic and Promotes Antitumor Immunity.

Unlabelled: Cellular senescence is a stress response that activates innate immune cells, but little is known about its interplay with the adaptive immune system. Here, we show that senescent cells combine several features that render them highly efficient in activating dendritic cells (DC) and antigen-specific CD8 T cells. This includes the release of alarmins, activation of IFN signaling, enhanced MHC class I machinery, and presentation of senescence-associated self-peptides that can activate CD8 T cells.

Immunosuppressive Mediators Impair Proinflammatory Innate Lymphoid Cell Function in Human Malignant Melanoma.

Innate lymphoid cells (ILC) are a family of immune cells that are emerging as potent orchestrators of immune responses. In cancer, ILCs display both pro- and antitumorigenic functions depending on the nature of the tumor and the involved ILC subset. Little is known about the ILC-tumor cross-talk in human melanoma.

Recognition of human gastrointestinal cancer neoantigens by circulating PD-1+ lymphocytes.

Tumor-resident lymphocytes can mount a response against neoantigens expressed in microsatellite-stable gastrointestinal (GI) cancers, and adoptive transfer of neoantigen-specific lymphocytes has demonstrated antitumor activity in selected patients. However, whether peripheral blood could be used as an alternative minimally invasive source to identify lymphocytes targeting neoantigens in patients with GI cancer with relatively low mutation burden is unclear. We used a personalized high-throughput screening strategy to investigate whether PD-1 expression in peripheral blood could be used to identify CD8+ or CD4+ lymphocytes recognizing neoantigens identified by whole-exome sequencing in 7 patients with GI cancer.

Determinants for Neoantigen Identification.

All tumors accumulate genetic alterations, some of which can give rise to mutated, non-self peptides presented by human leukocyte antigen (HLA) molecules and elicit T-cell responses. These immunogenic mutated peptides, or neoantigens, are foreign in nature and display exquisite tumor specificity. The correlative evidence suggesting they play an important role in the effectiveness of various cancer immunotherapies has triggered the development of vaccines and adoptive T-cell therapies targeting them.

Extracellular Influences: Molecular Subclasses and the Microenvironment in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form of pancreatic cancer and carries the worst prognosis of all common cancers. Five-year survival rates have not surpassed 6% for some decades and this lack of improvement in outcome urges a better understanding of the PDAC-specific features which contribute to this poor result. One of the most defining features of PDAC known to contribute to its progression is the abundance of non-tumor cells and material collectively known as the stroma.

Snail1 transcription factor controls telomere transcription and integrity.

Besides controlling epithelial-to-mesenchymal transition (EMT) and cell invasion, the Snail1 transcriptional factor also provides cells with cancer stem cell features. Since telomere maintenance is essential for stemness, we have examined the control of telomere integrity by Snail1. Fluorescence in situ hybridization (FISH) analysis indicates that Snail1-depleted mouse mesenchymal stem cells (MSC) have both a dramatic increase of telomere alterations and shorter telomeres.

Metabolic responses in root nodules of Phaseolus vulgaris and Vicia sativa exposed to the imazamox herbicide.

Alterations on growth, amino acids metabolism and some antioxidant enzyme activities as result of imazamox treatment were examined in determinate and indeterminate nodules, formed by Phaseolus vulgaris and Vicia sativa, respectively. Young seedlings of both legumes were inoculated with their respective microsymbionts and grown under controlled conditions. At vegetative growth, plants were treated with imazamox (250μM) in the nutrient solution and harvested 7days after.

Physiological and biochemical responses of common vetch to the imazamox accumulation.

Common vetch (Vicia sativa L.) is a forage and grain legume, widely distributed throughout the world. Alterations induced by the herbicide imazamox on plant growth, acetohydroxyacid synthase activity, total free amino acids, as well as concentrations of valine, leucine, isoleucine and imazamox in young and mature leaves were investigated at 2 and 7 days after the herbicide application.