A Phase 1/1B Trial of Pembrolizumab and Trametinib in Advanced NSCLC Enriched for KRAS Mutations.

Introduction: MEK inhibition (MEKi) combined with programmed death ligand 1 inhibition (immune checkpoint inhibitor [ICI]) modulates the tumor immune microenvironment. This phase 1 study evaluated sequencing schemes of MEKi and ICI with trametinib and pembrolizumab in NSCLC.

Methods: In this 3+3 dose escalation study, patients with advanced NSCLC were treated with lead-in trametinib (arm A) or lead-in pembrolizumab (arm B) for cycle 1, followed by a 1.

IL-4 mediated TAP2 downregulation is a dominant and reversible mechanism of immune evasion and immunotherapy resistance in non-small cell lung cancer.

Background: Resistance to both naturally occurring anti-cancer immunity and to immunotherapy is common in patients with aggressive non-small cell lung cancer (NSCLC). Recent studies indicate a role of loss of the HLA class-I antigen presentation machinery (APM) protein β-2-microglobulin in acquired resistance to immune checkpoint blockers. However, the mechanisms, functional consequences and therapeutic potential of APM defects in NSCLC remain poorly understood.

Biological and clinical significance of tumour-infiltrating lymphocytes in the era of immunotherapy: a multidimensional approach.

Immune-checkpoint inhibitors (ICIs) have improved clinical outcomes across several solid tumour types. Prominent efforts have focused on understanding the anticancer mechanisms of these agents, identifying biomarkers of response and uncovering resistance mechanisms to develop new immunotherapeutic approaches. This research has underscored the crucial roles of the tumour microenvironment and, particularly, tumour-infiltrating lymphocytes (TILs) in immune-mediated tumour elimination.

Distinct genomic and immunologic tumor evolution in germline -driven breast cancers.

Pathogenic germline alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of with no recurrent oncogenic variants except (HER2) amplification.

Objective Analysis and Clinical Significance of the Spatial Tumor-Infiltrating Lymphocyte Patterns in Non-Small Cell Lung Cancer.

Purpose: The spatial arrangement of lymphocytes in the tumor bed (e.g., immune infiltrated, immune excluded, immune desert) is expected to reflect distinct immune evasion mechanisms and to associate with immunotherapy outcomes.

Role of tumor infiltrating lymphocytes and spatial immune heterogeneity in sensitivity to PD-1 axis blockers in non-small cell lung cancer.

Background: Tumor infiltrating lymphocytes (TILs) reflect adaptive antitumor immune responses in cancer and are generally associated with favorable prognosis. However, the relationships between TILs subsets and their spatial arrangement with clinical benefit from immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) remains less explored.

Methods: We used multiplexed quantitative immunofluorescence panels to determine the association of major TILs subpopulations, CD8 cytotoxic T cells, CD4 helper T cells and CD20 B cells, and T cell exhaustion markers, programmed cell death protein-1 (PD-1),lymphocyte-activation gene 3 (LAG-3) and T cell immunoglobulin mucin-3 (TIM-3) with outcomes in a multi-institutional cohort of baseline tumor samples from 179 patients with NSCLC treated with ICI.

Tumour antigen-induced T cell exhaustion - the archenemy of immune-hot malignancies.

Two recent studies addressed the functional properties and clinical significance of tumour antigen-specific effector T cells in human melanomas and lung carcinomas using single-cell strategies. Herein, we discuss their findings, which expand our understanding of T cell alterations in the tumour microenvironment and demonstrate that CD8 T cell exhaustion is mediated by exposure to tumour cell-specific antigens and is associated with a tissue-resident memory phenotype.

Functional transcriptomic annotation and protein-protein interaction analysis identify EZH2 and UBE2C as key upregulated proteins in ovarian cancer.

Although early stage ovarian cancer is in most cases a curable disease, some patients relapse even with appropriate adjuvant treatment. Therefore, the identification of patient and tumor characteristics to better stratify risk and guide rational drug development is desirable. Using transcriptomic functional annotation followed by protein-protein interacting (PPI) network analyses, we identified functions that were upregulated and associated with detrimental outcome in patients with early stage ovarian cancer.