Chemokine in Anti-Tumor Immune Response

Chemokines are chemotactic cytokines belonging to a large family of small, secreted proteins that stimulate the cells migration and the positioning and interactions of cells within tissue. About 50 endogeneous chemokine ligands and 20 cell surface G protein-coupled heptahelicalchemokine receptors together form the chemokine superfamily. Chemokines regulate leukocyte migration into the tumor microenvironment and thus play important roles in deciding tumor fate, promoting anti-tumor immune responses, or sustaining tumor growth, angiogenesis and metastasis (Ref.1).

Chemokines mediate anti-tumor activities through inhibition of angiogenesis and attraction of immune effector cells to the tumor site. Major immune cells that are recruited to the tumor microenvironment (TME) include dendritic cells (DCs), CD4+TH1 cells, and CD8+ T effector cells.  Besides NK cells, Gamma delta T cells (γδ T cells), B-cells and immature Ddendrictic cells are also recruited by chemokines like CCL20/CCR6.  CXCL9 and CXCL10 may also promote the recruitment TH1 lymphocytes, NK cells, and CD8+ cytotoxic T lymphocytes by exerting a potent antitumor activity. Chemokine receptors like CCR4, CCR5, CXCR3, CXCR4, CCR6, and CCR7 play a major role in the regulation of T cell homing to inflammatory sites. , Cytotoxic T Lymphocyte specific for tumor-associated antigens (TAA), along with TH1 and NK cells guide immunity against the tumor promoting tumor cell apoptosis, and release effector cytokines and cytotoxic molecules. Tregs, CD4T helper, activated T cells, monocyte-derived dendritic cells (mDC) and B cells are also recruited by CCL19 and CCL21 through CCR7.  DC interaction with CD4 T cell can cause release of CCL3, and CCL4 that are mainly responsible for recruitment of CCR5-positive naïve CD8+T cells into tissues for activation. CCL3 and CCL4 interaction with CCR5 receptor is necessary for the initiation of a specific immune response. Th17 and Th1 cells are present in the early stages, associated with an anti-tumor immune response and production of CXCL9 and CXCL10. Tumor associated macrophages (TAM) are also a source of CXCL9 and CXCL12.  Chemokines recruited TAM may polarize to form M1 macrophage that produce CXCL9/10 and exert an anti-tumor activity. N1 phenotype formed from Tumor associated neutrophils (TAN) exerts an anti-tumoral activity (Ref.2 and 3).

Naive CD4+ T cell can stimulate tumor-specific immunity by differentiating into several subsets. Conventional TCR α/β CD4+ T cell subsets mainly contribute to anti-tumor immunity by antigen peptide recognition (Ref.4). On the other hand, the anti-tumor function of CD8+ T cells depends on two crucial factors: CD8+ T cell differentiation and CD8+ T cell infiltration into the tumor site which occurs by trafficking or transporting CD8+ T cells into the tumor microenvironment (Ref.5). Chemokines have limited anti-tumor activity when acting alone but as an adjuvant its anti-tumor activity increases.  In combination with cytokines like interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GCSF), anti-tumor activity of chemokines is enhanced (Ref.6).