Immune Modulatory Properties of Collagen in Cancer

During tumor growth the extracellular matrix (ECM) undergoes dramatic remodeling. The normal ECM is degraded and substituted with a tumor-specific ECM, which is often of higher collagen density and increased stiffness. The structure and collagen density of the tumor-specific ECM has been associated with poor prognosis in several types of cancer. However, the reason for this association is still largely unknown. Collagen can promote cancer cell growth and migration, but recent studies have shown that collagens can also affect the function and phenotype of various types of tumor-infiltrating immune cells such as tumor-associated macrophages (TAMs) and T cells. This suggests that tumor-associated collagen could have important immune modulatory functions within the tumor microenvironment, affecting cancer progression as well as the efficacy of cancer immunotherapy. The effects of tumor-associated collagen on immune cells could help explain why a high collagen density in tumors is often correlated with a poor prognosis. Knowledge about immune modulatory functions of collagen could potentially identify targets for improving current cancer therapies or for development of new treatments. In this review, the current knowledge about the ability of collagen to influence T cell activity will be summarized. This includes direct interactions with T cells as well as induction of immune suppressive activity in other immune cells such as macrophages. Additionally, the potential effects of collagen on the efficacy of cancer immunotherapy will be discussed.

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Innate Immune Cells and Their Contribution to T-Cell-Based Immunotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms21124441 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4441 ◽

Cited By ~ 1

Author(s):

Pierpaolo Ginefra ◽

Girieca Lorusso ◽

Nicola Vannini

Keyword(s):

T Cells ◽

T Cell ◽

Cancer Immunotherapy ◽

Cancer Patients ◽

Immune Cells ◽

Adoptive Cell Therapy ◽

Adaptive Immune Response ◽

Immune Checkpoint Blockade ◽

Innate Immune ◽

Innate Immune Cells

In recent years, immunotherapy has become the most promising therapy for a variety of cancer types. The development of immune checkpoint blockade (ICB) therapies, the adoptive transfer of tumor-specific T cells (adoptive cell therapy (ACT)) or the generation of T cells engineered with chimeric antigen receptors (CAR) have been successfully applied to elicit durable immunological responses in cancer patients. However, not all the patients respond to these therapies, leaving a consistent gap of therapeutic improvement that still needs to be filled. The innate immune components of the tumor microenvironment play a pivotal role in the activation and modulation of the adaptive immune response against the tumor. Indeed, several efforts are made to develop strategies aimed to harness innate immune cells in the context of cancer immunotherapy. In this review, we describe the contribution of innate immune cells in T-cell-based cancer immunotherapy and the therapeutic approaches implemented to broaden the efficacy of these therapies in cancer patients.

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APOC1 is a Potential Prognostic Biomarker and Correlated With Immune Infiltration in ESCC

10.21203/rs.3.rs-98085/v1 ◽

2020 ◽

Author(s):

Jia-yi XIE ◽

Ming Liu ◽

Yaxin Luo ◽

Zhen Wang ◽

Zhenghong Lu ◽

...

Keyword(s):

T Cells ◽

Transcription Factors ◽

Cd8 T Cells ◽

Immune Cells ◽

Poor Prognosis ◽

Killer Cell ◽

Gene Set Enrichment Analysis ◽

Immune Infiltration ◽

Kaplan Meier ◽

Kaplan Meier Plotter

Abstract PurposeEsophageal cancer (EC) is the sixth leading cause of cancer death worldwide. Esophageal squamous cell carcinoma (ESCC) is a predominant subtype of EC. Identifying diagnostic biomarkers for ESCC is necessary for cancer practice. Increasing evidence illustrates that apolipoprotein C-1 (APOC1) participates in the carcinogenesis. However, the biological function of APOC1 in ESCC remains unclear. Patients and methodsWe investigated the expression level of APOC1 using TIMER2.0 and GEO databases, the prognostic value of APOC1 in ESCC using Kaplan-Meier plotter and TCGA databases. We used LinkedOmics to identify co-expressed genes with APOC1 and perform GO and KEGG pathway analysis. The target networks of kinases, miRNAs and transcription factors were predicted by gene set enrichment analysis (GSEA). The correlations between APOC1 and immune infiltration were calculated using TIMER2.0 and CIBERSORT databases. We further performed the prognostic analysis based on APOC1 expression levels in related immune cells subgroups via Kaplan-Meier plotter database. ResultsAPOC1 was found overexpressed in tumor tissues in multiple ESCC cohorts and high APOC1 expression was related to a dismal prognosis. Multivariate analysis confirmed that APOC1 overexpression was an independent indicator of poor OS. Functional network analysis indicated that APOC1 might regulate the natural killer cell mediated cytotoxicity, phagosome, AMPK and hippo signaling through pathways involving some cancer-related kinases, miRNA and transcription factors. Immune infiltration analysis showed that APOC1 was significantly positively correlated with M0 macrophages cells, M1 macrophages cells and activated NK cells, negatively correlated with regulatory T cells, CD8 T cells, neutrophils and monocytes. High APOC1 expression had a poor prognosis in server immune cells subgroups in ESCC, including decreased CD8+ T cells subgroups. ConclusionThese findings suggest that increased expression of APOC1 is related to poor prognosis and immune infiltration in ESCC. APOC1 holds promise for serving as a valuable diagnostic and prognostic marker in ESCC.

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Low TWEAK expression indicates poor survival and is correlated with sparse TIICs in lung adenocarcinoma (LUAD).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21017 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21017-e21017

Author(s):

Jinchun Wu ◽

Xianyu Liu ◽

Yanhua Mou ◽

Shan Zeng ◽

Jin Zhang ◽

...

Keyword(s):

T Cells ◽

Lung Adenocarcinoma ◽

Cd8 T Cells ◽

Immune Cells ◽

Poor Prognosis ◽

Immune Escape ◽

Underlying Mechanism ◽

Memory Cd8 T Cells ◽

Kaplan Meier ◽

Kaplan Meier Plotter

e21017 Background: Lung adenocarcinoma (LUAD) occupies the most of non-small cell lung cancer (NSCLC) and shows promising response to PD-1 immunotherapy, but immune escape will cause treatment failure indicating poor prognosis. TWEAK (Tumor necrosis factor-related weak inducer of apoptosis, also known as TNFSF12) combining with its receptor FN14 (fibroblast growth factor–inducible 14) mediates crucial innate and adaptive immune pathways to promote the progression of multiple autoimmune diseases. So we assumed that TWEAK is a prognostic predictor and related with tumor-infiltrating immune cells (TIICs) in LUAD. Methods: TWEAK expression of LUAD was primarily investigated in The Cancer Immunome Atlas (TCIA) and then validated in Tumor Immune Estimation Resource (TIMER) databases. We assessed the effect of TWEAK on the survival via the Kaplan-Meier plotter, GEPIA2 (gene expression profiling interactive analysis) and PrognoScan databases. The relation between TWEAK and TIICs was explored in TIMER and TCIA, as well as the correlation of TWEAK and FN14 was analyzed in TIMER and GEPIA2. Results: Low TWEAK expression was significantly associated with poor relapse-free survival (RFS) (HR = 0.62, 95% CI = 0.4~0.97, logrank P = 0.035) and overall survival (OS) (HR = 0.61, 95% CI = 0.46~0.83, logrank P = 0.0012) in LUAD from Kaplan-Meier plotter. Similar impacts of TWEAK on the survival were validated in GEPIA2 and four independent cohorts from PrognoScan (jacob-00182-CANDF, GSE13213, jacob-00182-MSK and GSE31210). Moreover, reduced TWEAK expression was closely related with the paucity of TIICs which contributed to poor OS, including central memory CD8 T cells, plasmacytoid dendritic cells, activated CD8 T cells, monocytes, T follicular helper cells, immature B cells and eosinophils. In addition, TWEAK expression was positively related with the expression level of FN14 in both GEPIA2(R = 0.13, P= 0.0031) and TIMER (partial.cor = 0.212, P= 2.04e-06). Conclusions: Low TWEAK expression maybe indicate poor prognosis in LUAD, and correlated with the impaired infiltration of immune cells in the tumor region. The defective TWEAK/FN14 pathway possibly accounts for these observations, but the underlying mechanism needs to be further explored.

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Single cell transcriptome atlas of immune cells in human small intestine and in celiac disease

10.1101/721258 ◽

2019 ◽

Cited By ~ 1

Author(s):

Nader Atlasy ◽

Anna Bujko ◽

Peter B Brazda ◽

Eva Janssen-Megens ◽

Espen S. Bækkevold ◽

...

Keyword(s):

T Cells ◽

Small Intestine ◽

Celiac Disease ◽

Single Cell ◽

Cd8 T Cells ◽

Immune Cells ◽

Current Knowledge ◽

Villous Atrophy ◽

Cellular Heterogeneity ◽

Human Small Intestine

Celiac disease (CeD) is an autoimmune disorder in which ingestion of dietary gluten triggers an immune reaction in the small intestine1,2. The CeD lesion is characterized by crypt hyperplasia, villous atrophy and chronic inflammation with accumulation of leukocytes both in the lamina propria (LP) and in the epithelium3, which eventually leads to destruction of the intestinal epithelium1 and subsequent digestive complications and higher risk of non-hodgkin lymphoma4. A lifetime gluten-free diet is currently the only available treatment5. Gluten-specific LP CD4 T cells and cytotoxic intraepithelial CD8+ T cells are thought to be central in disease pathology1,6-8, however, CeD is a complex immune-mediated disorder and to date the findings are mostly based on analysis of heterogeneous cell populations and on animal models. Here, we comprehensively explore the cellular heterogeneity of CD45+ immune cells in human small intestine using index-sorting single-cell RNA-sequencing9,10. We find that myeloid and mast cell transcriptomes are reshaped in CeD. We observe extensive changes in the proportion and transcriptomes of CD4+ and CD8+ T cells and define a CD3zeta expressing NK-T-like cell population present in the control LP and epithelial layers that is absent and replaced in CeD. Our findings show that the immune landscape is dramatically changed in active CeD which provide new insights and considerably extend the current knowledge of CeD immunopathology.

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Low Levels of T Cell Exhaustion in Tuberculous Lung Granulomas

Infection and Immunity ◽

10.1128/iai.00426-18 ◽

2018 ◽

Vol 86 (9) ◽

Cited By ~ 12

Author(s):

Eileen A. Wong ◽

Louis Joslyn ◽

Nicole L. Grant ◽

Edwin Klein ◽

Philana Ling Lin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Cells ◽

Cell Function ◽

Cell Activity ◽

Intrinsic Property ◽

T Cell Exhaustion ◽

Inhibitory Receptors ◽

Content Type ◽

Cell Exhaustion

ABSTRACTThe hallmarks of pulmonaryMycobacterium tuberculosisinfection are lung granulomas. These organized structures are composed of host immune cells whose purpose is to contain or clear infection, creating a complex hub of immune and bacterial cell activity, as well as limiting pathology in the lungs. Yet, given cellular activity and the potential for frequent interactions between host immune cells andM. tuberculosis-infected cells, we observed a surprisingly low quantity of cytokine-producing T cells (<10% of granuloma T cells) in our recent study ofM. tuberculosisinfection within nonhuman primate (NHP) granulomas. Various mechanisms could limit T cell function, and one hypothesis is T cell exhaustion. T cell exhaustion is proposed to result from continual antigen stimulation, inducing them to enter a state characterized by low cytokine production, low proliferation, and expression of a series of inhibitory receptors, the most common being PD-1, LAG-3, and CTLA-4. In this work, we characterized the expression of inhibitory receptors on T cells and the functionality of these cells in tuberculosis (TB) lung granulomas. We then used these experimental data to calibrate and inform an agent-based computational model that captures environmental, cellular, and bacterial dynamics within granulomas in lungs duringM. tuberculosisinfection. Together, the results of the modeling and the experimental work suggest that T cell exhaustion alone is not responsible for the low quantity ofM. tuberculosis-responsive T cells observed within TB granulomas and that the lack of exhaustion is likely an intrinsic property of granuloma structure.

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Sphingosine-1-Phosphate Catabolizing Enzymes Predict Better Prognosis in Triple-Negative Breast Cancer Patients and Correlates With Tumor-Infiltrating Immune Cells

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.697922 ◽

2021 ◽

Vol 8 ◽

Author(s):

Rajeev Nema ◽

Ashok Kumar

Keyword(s):

Breast Cancer ◽

T Cells ◽

Cd8 T Cells ◽

Immune Cells ◽

Poor Prognosis ◽

Triple Negative ◽

Strong Positive Correlation ◽

Breast Cancer Patients ◽

Sphingosine 1 Phosphate ◽

S1p Receptor

Background: Triple-negative breast cancer (TNBC) is associated with a poor prognosis. Sphingosine-1-phosphate (S1P), a potent sphingolipid metabolite, has been implicated in many processes that are important for breast cancer (BC). S1P signaling regulates tumorigenesis, and response to chemotherapy and immunotherapy by affecting the trafficking, differentiation or effector function of tumor-infiltrating immune cells (TIICs).Objective: In this study, using bioinformatics tools and publicly available databases, we have analyzed the prognostic value of S1P metabolizing genes and their correlation with TIICs in BC patients.Methods: The expression of S1P metabolizing genes and receptors was evaluated by the UALCAN cancer database. The correlation between mRNA expression of S1P metabolizing genes and receptors and survival outcome of breast cancer patients was analyzed by the Kaplan-Meier plotter database. The association between the gene expression and infiltration of immune cells in the tumors was analyzed by “Tumor-Infiltrating Immune Estimation Resource (TIMER). In silico protein expression analysis was done using the Human Protein Atlas” database.Results: TNBC patients with lower expression of S1P phosphatase 1 (SGPP1) or lipid phosphate phosphatase 3 (PLPP3) have much shorter relapse-free survival than the patients with a higher expression of these genes. SGPP1 and PLPP3 expression show a strong positive correlation with tumor-infiltrating dendritic cells (DCs), CD4+ and CD8+ T cells, neutrophils, and macrophages in the TNBC subtypes. In addition, S1P receptor 4 (S1PR4), an S1P receptor exhibit a strong positive correlation with DCs, CD4+ and CD8+ T cells and neutrophils in TNBC. We, therefore, conclude that low expression of SGPP1 and PLPP3 may hinder the recruitment of immune cells to the tumor environment, resulting in the blockage of cancer cell clearance and a subsequent poor prognosis.

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Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity

Experimental & Molecular Medicine ◽

10.1038/s12276-020-00500-y ◽

2020 ◽

Vol 52 (9) ◽

pp. 1475-1485 ◽

Cited By ~ 3

Author(s):

Won Suk Lee ◽

Hannah Yang ◽

Hong Jae Chon ◽

Chan Kim

Keyword(s):

T Cells ◽

T Cell ◽

Cancer Immunotherapy ◽

Immune Cells ◽

Immune Checkpoint ◽

Uterine Cancer ◽

Tumor Vessels ◽

Angiogenic Therapy ◽

Cancer Immunity ◽

Adaptive Immune Cells

Abstract Cancer immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced cancers. However, the tumor microenvironment (TME) functions as a formidable barrier that severely impairs the efficacy of ICIs. While the crosstalk between tumor vessels and immune cells determines the nature of anti-tumor immunity, it is skewed toward a destructive cycle in growing tumors. First, the disorganized tumor vessels hinder CD8+ T cell trafficking into the TME, disable effector functions, and even kill T cells. Moreover, VEGF, the key driver of angiogenesis, interferes with the maturation of dendritic cells, thereby suppressing T cell priming, and VEGF also induces TOX-mediated exhaustion of CD8+ T cells. Meanwhile, a variety of innate and adaptive immune cells contribute to the malformation of tumor vessels. Protumoral M2-like macrophages as well as TH2 and Treg cells secrete pro-angiogenic factors that accelerate uncontrolled angiogenesis and promote vascular immaturity. While CD8+ T and CD4+ TH1 cells suppress angiogenesis and induce vascular maturation by secreting IFN-γ, they are unable to infiltrate the TME due to malformed tumor vessels. These findings led to preclinical studies that demonstrated that simultaneous targeting of tumor vessels and immunity is a viable strategy to normalize aberrant vascular-immune crosstalk and potentiate cancer immunotherapy. Furthermore, this combination strategy has been evidently demonstrated through recent pivotal clinical trials, granted approval from FDA, and is now being used in patients with kidney, liver, lung, or uterine cancer. Overall, combining anti-angiogenic therapy and ICI is a valid therapeutic strategy that can enhance cancer immunity and will further expand the landscape of cancer treatment.

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Association of Th2 high tumors with aggressive features of breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e12584 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e12584-e12584

Author(s):

Yoshihisa Tokumaru ◽

Lan Le ◽

Masanori Oshi ◽

Eriko Katsuta ◽

Nobuhisa Matsuhashi ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Cancer Progression ◽

Immune Cells ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Th2 Cells ◽

Immune Microenvironment ◽

Adaptive Immune Cells ◽

Tumor Immune Microenvironment

e12584 Background: Recent studies have shown that infiltrating T-lymphocytes have been implicated in the promotion of breast cancer progression. Upon activation, these antigen-presenting cells then recruit adaptive immune cells. It has been proposed that polarization of CD4+ effector T-cells towards the immunosuppressive Th2 cells induce cytokine release and T-cell anergy, which lead to polarization of M2 tumor-associated macrophages (TAM’s), providing a protumorigenic microenvironment. We hypothesized that there is a correlation between high levels of Th2 cells and aggressive features of breast cancer and unfavorable tumor immune environment. Methods: Clinicopathological data and overall survival information was obtained on 1069 breast cancer patients from The Cancer Genome Atlas (TCGA) database. We defined Th2 high and low levels with the median cutoff. Results: Analysis of cell composition of the immune cells within tumor immune microenvironment demonstrated that Th2 high tumors did not consistently associated with unfavorable tumor immune microenvironment. Pro-cancer immune cells, such as macrophage M2 cells were increased with Th2 high tumors whereas, regulatory T cells were decreased with Th2 high tumors (p < 0.01 and p < 0.001 respectively). On the contrary, infiltration of anti-cancer cells, such as macrophage M1 was increased whereas CD8 T cells were decreased with Th2 high tumors (p < 0.05 and p < 0.001 respectively). Th2 was not shown to have correlation with IL-4, IL-6, IL-10 and IL-13, all of which has been reported to associate with Th2 cells. Th2 levels were associated with advanced grades. Also, correlation analysis demonstrated that there was a strong correlation between Th2 levels and Ki-67. These results were further validated with gene set enrichment analysis (GSEA). GSEA revealed that in Th2 high tumors enriched the gene sets associated with cell proliferation and cell cycle. Conclusions: High expression of immunosuppressive Th2 cells was associated with highly proliferative features of breast cancer, but not with unfavorable tumor immune microenvironment.

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Natural Compounds with Potential to Modulate Cancer Therapies and Self-Reactive Immune Cells

Cancers ◽

10.3390/cancers12030673 ◽

2020 ◽

Vol 12 (3) ◽

pp. 673 ◽

Cited By ~ 1

Author(s):

Rhiane Moody ◽

Kirsty Wilson ◽

Anthony Jaworowski ◽

Magdalena Plebanski

Keyword(s):

Ovarian Cancer ◽

T Cells ◽

Immune Cells ◽

Epigallocatechin Gallate ◽

Cancer Recurrence ◽

Cancer Therapies ◽

Dna Mutations ◽

Autoimmune Pathology ◽

Therapy Option ◽

New Treatments

Cancer-related deaths are approaching 10 million each year. Survival statistics for some cancers, such as ovarian cancer, have remained unchanged for decades, with women diagnosed at stage III or IV having over 80% chance of a lethal cancer recurrence after standard first-line treatment (reductive surgery and chemotherapy). New treatments and adjunct therapies are needed. In ovarian cancer, as in other cancers, the immune response, particularly cytotoxic (CD8+) T cells are correlated with a decreased risk of recurrence. As well as completely new antigen targets resulting from DNA mutations (neo-antigens), these T cells recognize cancer-associated overexpressed, re-expressed or modified self-proteins. However, there is concern that activation of self-reactive responses may also promote off-target pathology. This review considers the complex interplay between cancer-reactive and self-reactive immune cells and discusses the potential uses for various leading immunomodulatory compounds, derived from plant-based sources, as a cancer therapy option or to modulate potential autoimmune pathology. Along with reviewing well-studied compounds such as curcumin (from turmeric), epigallocatechin gallate (EGCG, from green tea) and resveratrol (from grapes and certain berries), it is proposed that compounds from novel sources, for example, native Australian plants, will provide a useful source for the fine modulation of cancer immunity in patients.

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Collagen density regulates the activity of tumor-infiltrating T cells

10.1101/493437 ◽

2018 ◽

Author(s):

Dorota E Kuczek ◽

Anne Mette H Larsen ◽

Marco Carretta ◽

Adrija Kalvisa ◽

Majken S Siersbæk ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Density Matrix ◽

Cancer Cells ◽

Cd8 T Cells ◽

Cell Activity ◽

High Density ◽

Collagen Density ◽

Whole Transcriptome

AbstractBackgroundTumor progression is accompanied by dramatic remodeling of the surrounding extracellular matrix leading to the formation of a tumor-specific ECM, which is often more collagen-rich and of increased stiffness. The altered ECM of the tumor supports cancer growth and metastasis, but it is unknown if this effect involves modulation of T cell activity. To investigate if a high-density tumor-specific ECM could influence the ability of T cells to kill cancer cells, we here studied how T cells respond to 3D culture in different collagen densities.MethodsT cells cultured in 3D conditions surrounded by a high or low collagen density were imaged using confocal fluorescent microscopy. The effects of the different collagen densities on T cell proliferation, survival, and differentiation were examined using flow cytometry. Cancer cell proliferation in similar 3D conditions was also measured. Triple-negative breast cancer specimens were analyzed for the number of infiltrating CD8+ T cells and for the collagen density. Whole-transcriptome analyses were applied to investigate in detail the effects of collagen density on T cells. Computational analyses were used to identify transcription factors involved in the collagen density-induced gene regulation. Observed changes were confirmed by qRT-PCR analysis.ResultsT cell proliferation was significantly reduced in a high-density matrix compared to a low-density matrix and prolonged culture in a high-density matrix led to a higher ratio of CD4+ to CD8+ T cells. The proliferation of cancer cells was unaffected by the surrounding collagen-density. Consistently, we observed a reduction in the number of infiltrating CD8+ T-cells in mammary tumors with high collagen-density indicating that collagen-density has a role in regulating T cell abundance in human breast cancer.Whole-transcriptome analysis of 3D-cultured T cells revealed that a high-density matrix induces downregulation of cytotoxic activity markers and upregulation of regulatory T cell markers. These transcriptional changes were predicted to involve autocrine TGF-B signaling and they were accompanied by an impaired ability of tumor-infiltrating T cells to kill autologous cancer cells.ConclusionsOur study identifies a new immune modulatory mechanism, which could be essential for suppression of T cell activity in the tumor microenvironment.

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