Cancer Biology III Tumor Microenvironment (TME) PDF

Cancer Biology III Tumor Microenvironment (TME) Leow Chiuan Yee, PhD School of Pharmaceutical Sciences Universiti Sains Malaysia 1  Learning Outcomes...

Cancer Biology III Tumor Microenvironment (TME) Leow Chiuan Yee, PhD School of Pharmaceutical Sciences Universiti Sains Malaysia 1  Learning Outcomes We l e a d Tumor microenvironment (TME) Key components of the TME Association of TME in cancer development Immune evasion strategies used by tumor cells Interaction between costimulatory and immune checkpoint ligand-receptor 2  Tumor Microenvironment (TME) We l e a d The Tumor Microenvironment (TME) is the complex and dynamic environment surrounding a tumor, comprising various cells, signaling molecules, and the extracellular matrix. It plays a critical role in tumor development, progression, metastasis, and response to therapy. The interaction between cancer cells and the components of the TME significantly influences the behavior of the tumor. 3 Key components of the TME We l e a d 4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547015/  Key components of the TME We l e a d 1. Cancer Cells: The primary malignant cells that drive tumor growth and progression. 5 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547015/  Key components of the TME We l e a d 1. Cancer Cells: The primary malignant cells that drive tumor growth and progression. 2. Stromal Cells: Fibroblasts: Produce extracellular matrix components and secrete growth factors. Endothelial Cells: Form blood vessels that supply nutrients and oxygen to the tumor. Pericytes: Support and stabilize blood vessels. 6 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547015/  Key components of the TME We l e a d 3. Immune Cells: T Cells: Can attack cancer cells but often become suppressed or exhausted. Macrophages: Can be tumor-promoting (M2 type) or tumor-suppressing (M1 type). Tumor-associated macrophages (TAMs): promote tumor growth and metastasis by creating an immunosuppressive environment. Myeloid-Derived Suppressor Cells (MDSCs): Suppress the immune response. Dendritic Cells: Present antigens to T cells, initiating immune responses. Natural Killer (NK) Cells: Attack and kill cancer cells. 7 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547015/  Key components of the TME We l e a d 4. Blood Vessels and Angiogenesis Formation of new blood vessels to supply the growing tumor with nutrients and oxygen. Facilitated by endothelial cells and pericytes, often driven by VEGF (vascular endothelial growth factor). Essential for tumor growth beyond a certain size and a key pathway for metastasis. 8 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547015/  Key components of the TME We l e a d 5. Extracellular Matrix (ECM): Proteins like collagen, fibronectin, and proteoglycans. Provides structural support and regulates signaling pathways. Altered ECM can enhance tumor cell proliferation, migration, and invasion. 9 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547015/  Key components of the TME We l e a d 6. Signaling Molecules Cytokines, chemokines, growth factors (e.g., TGF-β, IL-6, IL-10, VEGF). Mediate communication between cancer cells and TME components. Support tumor growth, immune evasion, angiogenesis, and metastasis. 10 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547015/ Association of TME in cancer development We l e a d https://www.sciencedirect.com/science/article/pii/S0304419X21000846#bi0005 11  Association of TME in cancer development We l e a d The presence of CD4+ T helper 1, CD8+ T cells, natural killer cells, T lymphocytes, B cells, M1 macrophages and mature dendritic cells is correlated with immune control. On the other hand, the presence of CD4+ T helper 2, CD4+ regulatory T cells, M2 macrophages, neutrophils, cancer associated fibroblasts, immature dendritic cells and myeloid-derived suppressor cells forms a complex network that supports immune escape. https://www.sciencedirect.com/science/article/pii/S0304419X21000846#bi0005 Tumor hypoxia is another proangiogenic factor that is associated with poor prognosis as cancer cells have high metabolic demands, and new blood vessels are crucial to supply oxygen and nutrients to support their rapid growth. 12 Regulatory T cells (Tregs), M2 macrophages (MΦ), and myeloid-derived suppressor cells (MDSCs) are predominant in the immunosuppressive TME during tumor development.  Immune evasion strategies used by tumor cells We l e a d Cancer cells employ various strategies to evade the immune system, ensuring their survival and proliferation within the host. These strategies can be intrinsic to the cancer cells or facilitated by the TME. 15 Immune evasion strategies used by tumor cells We l e a d Abbreviations: APC, antigen-presenting cells; IL, interleukin; MDSCs, myeloid-derived suppressor cells; MHC, major histocompatibility complex; Tregs, T-regulatory cells. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3917949/#:~:text=Immunotherapies%20represent%20a%20novel%20approach,and%20may%20have%2 0broad%20applicability. 16 Immune evasion strategies used by tumor cells We l e a d A. Alteration of Antigen Presentation: Cancer cells can downregulate expression of MHC molecules that present tumor antigens to T-cells, and suppress tumor antigen presentation by professional APC, thereby avoiding recognition by T-cells. Thus, making it difficult for T cells to recognize and attack cancer cells. B. Recruitment of Immunosuppressive Cells: Tumors create an immunosuppressive environment by recruitment and retention of suppressive Tregs and MDSCs. Regulatory T Cells (Tregs): Suppress the immune response against cancer cells. Myeloid-Derived Suppressor Cells (MDSCs): Inhibit the function of T cells and NK cells. 17 Immune evasion strategies used by tumor cells We l e a d C. Secretion of Immunosuppressive Cytokines: Secretion of immune-regulating or suppressive cytokines (IL-4, IL-5, IL-6, IL-10, and IL- 13 and transforming growth factor-beta) and mediators (prostaglandins, indoleamine 2,3-dioxygenase by suppressive Tregs and MDSCs. Transforming Growth Factor-beta (TGF-β): Inhibits T cell proliferation and function. Interleukin-10 (IL-10): Suppresses the activity of T cells and NK cells. D. Expression of Immune Checkpoint Molecules: Dysregulation of T-cell checkpoint pathways, including expression of PD-L1 by tumors, sends negative signals to tumor-specific T cells, causing T cell inactivation. Binding of CTLA-4 to its ligands inhibits T cell activation. 18 Interaction between Costimulatory and Immune Checkpoint Ligand-receptor We l e a d Berglund, A. et. al., Experimental & Molecular Medicine (2021) Interaction between costimulatory and immune checkpoint ligand-receptor We l e a d Berglund, A. et. al., Experimental & Molecular Medicine (2021) Interaction between costimulatory and immune checkpoint ligand-receptor We l e a d Berglund, A. et. al., Experimental & Molecular Medicine (2021) Interaction between costimulatory and immune checkpoint ligand-receptor We l e a d Berglund, A. et. al., Experimental & Molecular Medicine (2021)  We l e a d Thank you! 23