Expand to shield: IL-15 and in situ lymphocytic proliferation

Abstract

The tumor microenvironment includes a complex network of cytokines and chemokines that contribute to shaping the intratumoral immune reaction. Understanding the mechanisms leading to immune-hot (Immunoscore-high) altered (excluded and immunosuppressed) and cold tumors are of critical importance for successful anti-cancer therapies. Two essential mechanisms are highlighted. Specific chemokines and adhesion molecules appeared to target and attract immune effector T cells to the tumor microenvironment and to specific regions within the tumor. These mechanisms are dependent upon intratumoral IL-15 expression. Decreased IL15 expression also affected the local proliferation of B and T lymphocytes. A comprehensive analysis revealed a major contribution of IL15 in shaping the tumor immune contexture. Thus, an in situ lymphocytic infiltration is mediated through chemokines and attraction inside or around the tumor microenvironment, and an IL15-mediated in situ lymphocytic proliferation, which expand the local pool of intratumoral cytotoxic CD8 T-cells are key determinants of the immune contexture. Increased IL15 expression and local proliferation of T-cells were associated with decreased risk of tumor recurrence and prolonged survival of cancer patients. These data provide further mechanisms to prioritize research and help in designing better therapeutic interventions.

Keywords: IL-15; T-cells; attraction; chemokine; chromosomal instability; colorectal cancer; immunity; immunoscore; prognosis; proliferation; survival; tumor microenvironment.

Figure 1.

Intrametastatic immune landscape. (a) an in situ lymphocytic infiltration is mediated through chemokines and attraction inside or around the tumor microenvironment. IL15, produced mainly by activated myeloid cells and tumor cells, activates cytotoxic CD8 T-cells and NK-cells, which together with Th1 cells produce IFNG, a major cytokine involved together with XCL1 in shaping a good immune contexture and in activating cDC1 cells. These activated cDC1 cells, by producing chemokines such as CXCL9/10 are attracting CXCR3+ cells, notably memory CD45RO+ T-cells, cytotoxic CD8 T-cells and NK-cells. (b) In parallel, IL15 is also inducing a direct in situ lymphocytic proliferation, which expand the local pool of intratumoral cytotoxic CD8 T-cells. IL15 and these proliferating CD8 T-cells were associated with prolonged survival in cancer patients