Project description:To evaluate the characteristics of the tumor immune-microenvironment in brain metastases of non-small-cell lung cancer (NSCLC), we investigated the immunophenotype of primary NSCLC and its brain metastasis.
Project description:Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intra-tumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the tumor microenvironment (TME) exhibits substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAF) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting an exceptionally poor prognosis. Together, our work provides the first comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLCs adaptable nature, opening possibilities for re-programming the intercellular communications that shape SCLC tumor states.
Project description:<p>The effectiveness of immunotherapy varies among patients with advanced non-small cell lung cancer (NSCLC). Here we investigated the baseline immune status in stage IV NSCLC patients treated with anti-PD-1 plus chemotherapy to understand the immune mechanisms and unveil systemic markers associated with treatment response. Responders had elevated frequencies of circulating T cells expressing CD69, TCF-1 and CXCR-3. In contrast, non-responders presented increased frequencies of CTLA-4, CD161 and IL-10 expressing CD4+ and CD8+ T cells. These systemic T cell immune profiles were mirrored in the tumor microenvironment of an independent cohort. Concurrent CTLA-4 and PD-1 blockade was able to reactivate an anti-tumor profile in T cells from non-responder patients, emphasizing the pivotal role of CTLA-4 in contributing to an immunosuppressive environment that hinders effective treatment in NSCLC. This work supports the implementation of personalized immunotherapies based on systemic immune biomarkers, offering a promising approach to enhance treatment outcomes in advanced NSCLC.</p>
Project description:T lymphocytes can efficiently counteract the growth of tumors within the tumor microenvironment. Specialized immune-interacting fibroblasts, termed fibroblastic reticular cells (FRC) are responsible for the formation of specialized niches promoting immune cell activation in secondary lymphoid organs and originate from embryonic progenitors. FRCs have also been identified in tertiary lymphoid structures (TLS) in tumor tissues. However, the identity and differentiation of TLS-associated FRC subsets that promote intra-tumoral T cell activity have remained unexplored. Here, we employed single cell RNA-sequencing of fibroblasts and immune cells, sampled from subpleural margin, central margin and unaffected lung tissue in non small cell lung cancer (NSCLC), demonstrating the formation of specific tumor T cell environments (TTEs) underpinned by CCL19-expressing FRCs. We detected tumor-specific FRC subsets namely CCL19-expressing TRCs and perivascular reticular cells (PRCs) interacting with intratumoral T cells, and thus regulating FRC differentiation and T cell activation. Our results highlight a remarkable functionality of FRCs to efficiently determine protective antitumoral T cell responses in NSCLC.
