It is now widely accepted that the tumor microenvironment plays a critical role in tumor progression and metastasis as well as in the development of therapeutic resistance. Understanding the complex, dynamic bidirectional interaction between cancer cells and their microenvironment is currently under intense investigation. The two prevalent cell types in the tumor microenvironment are immune cells and cancer-associated fibroblasts (CAFs). Clinical studies revealed that tumor-infiltrating lymphocytes are associated with earlier stages of tumor progression and good prognosis. However, the tumor-infiltrating myeloid precursors (macrophages, MDSCs, regulatory DCs and neutrophils) as well as CAFs are associated with advanced stages of tumor progression and poor prognosis. Moreover, tumor-infiltrated myeloid precursors and fibroblasts regulate tumor cell plasticity and stemness during the metastatic cascade.
Most recent studies suggest that tumor-promoting immune cells also establish pre-metastatic niches which suppress anti-tumor immunity while promoting disseminated tumor cell survival. This indicates that malignant cancer cells induce a dynamic stromal reaction, which both resists and promotes tumor progression. It is currently unknown how the stromal equilibrium is established and how the ratios of different stromal cell types affect tumor progression and response to therapy. Additionally, extracellular matrix secreted by stromal cells can directly compromise the efficacy of chemotherapy delivery by increasing interstitial pressure, impeding the diffusion of large molecular weight drugs or sequestering drugs. Although stromal cells are viewed as promising therapeutic targets, we still face significant challenges in developing adequate tools to modify the stromal environment in cancer. Several therapeutic approaches targeting stromal cells, including endothelial cells, hematopoietic cells, and CAFs, have been used with variable success. Antiangiogenic agents, such as bevacizumab, effectively prolong progression-free, but not overall, survival. Immunotherapies with antagonists to CTLA-4, PD-1, and PD-L1 have yielded remarkable results, including complete responses in chemoresistant cancers and long-term remissions in melanoma and lung cancer. However, only a small subset of patients responds to immunotherapy. A recent clinical trial of anti-PD-1 therapy in melanoma revealed that innately resistant tumors upregulate the stromal genes involved in mesenchymal transition, extracellular matrix remodeling, and wound healing, pointing to the possible role of CAFs in the immune escape. Methods to effectively target CAFs without toxicity to normal fibroblasts and stem cells are still in the early stages of development. These variable successes in targeting tumor stroma highlight the need to better understand the molecular characteristics of stromal cells to develop more precise and less toxic targeted therapies.
We welcome manuscripts focusing on: 1) the molecular understanding of the reciprocal interaction between tumor cells and their microenvironment; 2) identification of factors that play critical roles in iterative interactions between tumor and infiltrated cells; 3) the equilibrium between anti-tumor immunity and immunosuppression; 4) regulation of tumor plasticity and stemness by the tumor microenvironment; and 5) the establishment of the pre-metastatic niche.
It is now widely accepted that the tumor microenvironment plays a critical role in tumor progression and metastasis as well as in the development of therapeutic resistance. Understanding the complex, dynamic bidirectional interaction between cancer cells and their microenvironment is currently under intense investigation. The two prevalent cell types in the tumor microenvironment are immune cells and cancer-associated fibroblasts (CAFs). Clinical studies revealed that tumor-infiltrating lymphocytes are associated with earlier stages of tumor progression and good prognosis. However, the tumor-infiltrating myeloid precursors (macrophages, MDSCs, regulatory DCs and neutrophils) as well as CAFs are associated with advanced stages of tumor progression and poor prognosis. Moreover, tumor-infiltrated myeloid precursors and fibroblasts regulate tumor cell plasticity and stemness during the metastatic cascade.
Most recent studies suggest that tumor-promoting immune cells also establish pre-metastatic niches which suppress anti-tumor immunity while promoting disseminated tumor cell survival. This indicates that malignant cancer cells induce a dynamic stromal reaction, which both resists and promotes tumor progression. It is currently unknown how the stromal equilibrium is established and how the ratios of different stromal cell types affect tumor progression and response to therapy. Additionally, extracellular matrix secreted by stromal cells can directly compromise the efficacy of chemotherapy delivery by increasing interstitial pressure, impeding the diffusion of large molecular weight drugs or sequestering drugs. Although stromal cells are viewed as promising therapeutic targets, we still face significant challenges in developing adequate tools to modify the stromal environment in cancer. Several therapeutic approaches targeting stromal cells, including endothelial cells, hematopoietic cells, and CAFs, have been used with variable success. Antiangiogenic agents, such as bevacizumab, effectively prolong progression-free, but not overall, survival. Immunotherapies with antagonists to CTLA-4, PD-1, and PD-L1 have yielded remarkable results, including complete responses in chemoresistant cancers and long-term remissions in melanoma and lung cancer. However, only a small subset of patients responds to immunotherapy. A recent clinical trial of anti-PD-1 therapy in melanoma revealed that innately resistant tumors upregulate the stromal genes involved in mesenchymal transition, extracellular matrix remodeling, and wound healing, pointing to the possible role of CAFs in the immune escape. Methods to effectively target CAFs without toxicity to normal fibroblasts and stem cells are still in the early stages of development. These variable successes in targeting tumor stroma highlight the need to better understand the molecular characteristics of stromal cells to develop more precise and less toxic targeted therapies.
We welcome manuscripts focusing on: 1) the molecular understanding of the reciprocal interaction between tumor cells and their microenvironment; 2) identification of factors that play critical roles in iterative interactions between tumor and infiltrated cells; 3) the equilibrium between anti-tumor immunity and immunosuppression; 4) regulation of tumor plasticity and stemness by the tumor microenvironment; and 5) the establishment of the pre-metastatic niche.
