Landscape of cancer-associated fibroblasts identifies the secreted biglycan as a protumor and immunosuppressive factor in triple-negative breast cancer.
Zheng Shaoquan,Zou Yutian,Tang Yuhui,Yang Anli,Liang Jie-Ying,Wu Linyu,Tian Wenwen,Xiao Weikai,Xie Xinhua,Yang Lu,Xie Jindong,Wei Weidong,Xie Xiaoming
Cancer-associated fibroblasts (CAFs) are essential for tumor microenvironment remodeling and correlate with tumor progression. However, interactions between CAFs and tumor cells and immune cells in triple-negative breast cancer (TNBC) are still poorly explored. Here, we investigate the role of CAFs in TNBC and potential novel mediators of their functions. The clustering of classic markers was applied to estimate the relative abundance of CAFs in TNBC cohorts. Primary fibroblasts were isolated from normal and tumor samples. The RNA and culture medium of fibroblasts were subjected to RNA sequencing and mass spectrometry to explore the upregulated signatures in CAFs. Microdissection and single-cell RNA sequencing datasets were used to examine the expression profiles. CAFs were associated with hallmark signalings and immune components in TNBC. Clustering based on CAF markers in the literature revealed different CAF infiltration groups in TNBC: low, medium and high. Most of the cancer hallmark signaling pathways were enriched in the high CAF infiltration group. Furthermore, RNA sequencing and mass spectrometry identified biglycan (BGN), a soluble secreted protein, as upregulated in CAFs compared to normal cancer-adjacent fibroblasts (NAFs). The expression of biglycan was negatively correlated with CD8 + T cells. Biglycan indicated poor prognostic outcomes and might be correlated with the immunosuppressive tumor microenvironment (TME). In conclusion, CAFs play an essential role in tumor progression and the TME. We identified an extracellular protein, biglycan, as a prognostic marker and potential therapeutic target in TNBC.
A Cancer Associated Fibroblasts-Related Six-Gene Panel for Anti-PD-1 Therapy in Melanoma Driven by Weighted Correlation Network Analysis and Supervised Machine Learning.
Frontiers in medicine
Background:Melanoma is a highly aggressive skin cancer with a poor prognosis and mortality. Immune checkpoint blockade (ICB) therapy (e.g., anti-PD-1 therapy) has opened a new horizon in melanoma treatment, but some patients present a non-responsive state. Cancer-associated fibroblasts (CAFs) make up the majority of stromal cells in the tumor microenvironment (TME) and have an important impact on the response to immunotherapy. There is still a lack of identification of CAFs-related predictors for anti-PD-1 therapy, although the establishment of immunotherapy biomarkers is well underway. This study aims to explore the potential CAFs-related gene panel for predicting the response to anti-PD-1 therapy in melanoma patients and elucidating their potential effect on TME. Methods:Three gene expression datasets from melanoma patients without anti-PD-1 treatment, in a total of 87 samples, were downloaded from Gene Expression Omnibus (GEO) as the discovery sets (GSE91061) and validation sets (GSE78220 and GSE122220). The CAFs-related module genes were identified from the discovery sets by weighted gene co-expression network analysis (WGCNA). Concurrently, we utilized differential gene analysis on the discovery set to obtain differentially expressed genes (DEGs). Then, CAFs-related key genes were screened with the intersection of CAFs-related module genes and DEGs, succeeded by supervised machine learning-based identification. As a consequence of expression analysis, gene set enrichment analysis, survival analysis, staging analysis, TME analysis, and correlation analysis, the multidimensional systematic characterizations of the key genes were uncovered. The diagnostic performance of the CAFs-related gene panel was assessed by receiver operating characteristic (ROC) curves in the validation sets. Eventually, the CAFs-related gene panel was verified by the expression from the single-cell analysis. Results:The six-gene panel associated with CAFs were finally identified for predicting the response to anti-PD-1 therapy, including , and . The multigene panel demonstrated excellent combined diagnostic performance with the area under the curve of ROC reaching 90.5 and 75.4% ~100% in the discovery and validation sets, respectively. Conclusion:Confirmed by clinical treatment outcomes, the identified CAFs-related genes can be used as a promising biomarker panel for prediction to anti-PD-1 therapy response, which may serve as new immunotherapeutic targets to improve survival outcomes of melanoma patients.
Prognostic Significance of Tumor-Infiltrating B Cells and Plasma Cells in Human Cancer.
Wouters Maartje C A,Nelson Brad H
Clinical cancer research : an official journal of the American Association for Cancer Research
There is abundant evidence that tumor-infiltrating CD8 T cells contribute positively to antitumor immunity; however, the role of tumor-infiltrating B cells (TIL-B) and plasma cells (PC) remains controversial, leading to differing opinions about whether immunotherapies should be designed to enhance or inhibit these cells. Through a comprehensive PubMed search, we reviewed publications with cohorts of 50 or more cases in which the prognostic value of TIL-B/PC was assessed by immunohistochemistry and/or gene-expression analysis. Sixty-nine studies representing 19 cancers met our review criteria. The large majority of studies assessed TIL-B by immunohistochemical detection of CD20. Of these, 50.0% reported a positive prognostic effect for CD20 TIL-B, whereas the remainder found a neutral (40.7%) or negative (9.3%) effect. These differences in prognostic effect were not attributable to cancer type, other clinicopathologic factors, or differing technical approaches. The prognostic significance of TIL-B/PC was generally concordant with that of CD3 and/or CD8 T cells, and the prognostic effect of T cells was generally stronger when TIL-B and/or PC were also present. Additionally, 21 studies inferred the presence of TIL-B/PC from gene-expression data, and a large majority reported a positive prognostic effect. Although more studies are required involving additional cancer types and independent patient cohorts, the weight of evidence supports a positive role for TIL-B and PC in antitumor immunity, suggesting that enhancement of these responses should be considered in the design of cancer immunotherapies.
B cells, plasma cells and antibody repertoires in the tumour microenvironment.
Sharonov George V,Serebrovskaya Ekaterina O,Yuzhakova Diana V,Britanova Olga V,Chudakov Dmitriy M
Nature reviews. Immunology
Recent data show that B cells and plasma cells located in tumours or in tumour-draining lymph nodes can have important roles in shaping antitumour immune responses. In tumour-associated tertiary lymphoid structures, T cells and B cells interact and undergo cooperative selection, specialization and clonal expansion. Importantly, B cells can present cognate tumour-derived antigens to T cells, with the functional consequences of such interactions being shaped by the B cell phenotype. Furthermore, the isotype and specificity of the antibodies produced by plasma cells can drive distinct immune responses. Here we summarize our current knowledge of the roles of B cells and antibodies in the tumour microenvironment. Moreover, we discuss the potential of using immunoglobulin repertoires as a source of tumour-specific receptors for immunotherapy or as biomarkers to predict the efficacy of immunotherapeutic interventions.
B Cell Function in the Tumor Microenvironment.
Annual review of immunology
The tumor microenvironment (TME) is a heterogeneous, complex organization composed of tumor, stroma, and endothelial cells that is characterized by cross talk between tumor and innate and adaptive immune cells. Over the last decade, it has become increasingly clear that the immune cells in the TME play a critical role in controlling or promoting tumor growth. The function of T lymphocytes in this process has been well characterized. On the other hand, the function of B lymphocytes is less clear, although recent data from our group and others have strongly indicated a critical role for B cells in antitumor immunity. There are, however, a multitude of populations of B cells found within the TME, ranging from naive B cells all the way to terminally differentiated plasma cells and memory B cells. Here, we characterize the role of B cells in the TME in both animal models and patients, with an emphasis on dissecting how B cell heterogeneity contributes to the immune response to cancer.
The Role of B Cells in Head and Neck Cancer.
Gavrielatou Niki,Vathiotis Ioannis,Economopoulou Panagiota,Psyrri Amanda
Head and neck cancer comprises a heterogenous, highly immune infiltrated malignancy, defined by a predominantly immunosuppressive tumor microenvironment (TME). In recent years, PD-1/PD-L1 immune checkpoint inhibitors have become the standard of care treatment, either as monotherapy or in combination with chemotherapy agents, thus revolutionizing the therapeutic landscape of recurrent/metastatic disease. As a result, preclinical research is increasingly focusing on TME composition and pathophysiology, aiming to comprehensively characterize the specific elements and interactions affecting anti-tumor immunity, as well as to unveil novel predictive biomarkers of immunotherapy outcomes. While T lymphocytic populations have been vastly explored regarding their effect on cancer development, B-cells constitute a far less investigated, yet possibly equally important, aspect of cancer immunity. B-cell presence, either as single cells or as part of tertiary lymphoid structures within the TME, has been associated with several anti-tumor defense mechanisms, such as antigen presentation, antibody production and participation in antibody-dependent cellular cytotoxicity, and has demonstrated prognostic significance for multiple types of malignancies. However, immunoregulatory B-cell phenotypes have also been identified both peripherally and within malignant tissue, bearing inhibitory effects on numerous immune response processes. Consequently, B-cells and their subsets demonstrate the potential to become valuable cancer biomarkers and acquire a leading role in future therapeutic strategies.
Actors on the Scene: Immune Cells in the Myeloma Niche.
Leone Patrizia,Solimando Antonio Giovanni,Malerba Eleonora,Fasano Rossella,Buonavoglia Alessio,Pappagallo Fabrizio,De Re Valli,Argentiero Antonella,Silvestris Nicola,Vacca Angelo,Racanelli Vito
Frontiers in oncology
Two mechanisms are involved in the immune escape of cancer cells: the immunoediting of tumor cells and the suppression of the immune system. Both processes have been revealed in multiple myeloma (MM). Complex interactions between tumor plasma cells and the bone marrow (BM) microenvironment contribute to generate an immunosuppressive milieu characterized by high concentration of immunosuppressive factors, loss of effective antigen presentation, effector cell dysfunction, and expansion of immunosuppressive cell populations, such as myeloid-derived suppressor cells, regulatory T cells and T cells expressing checkpoint molecules such as programmed cell death 1. Considering the great immunosuppressive impact of BM myeloma microenvironment, many strategies to overcome it and restore myeloma immunosurveillance have been elaborated. The most successful ones are combined approaches such as checkpoint inhibitors in combination with immunomodulatory drugs, anti-monoclonal antibodies, and proteasome inhibitors as well as chimeric antigen receptor (CAR) T cell therapy. How best to combine anti-MM therapies and what is the optimal timing to treat the patient are important questions to be addressed in future trials. Moreover, intratumor MM heterogeneity suggests the crucial importance of tailored therapies to identify patients who might benefit the most from immunotherapy, reaching deeper and more durable responses.