The immune response that unfolds within tumors largely determines the course of cancer, from precancerous lesions to late metastases, as well as patient survival. The cytotoxic and memory T lymphocytes that infiltrate the primary tumor are, particularly in colorectal cancer, the best predictors of this survival. This observation led to the concept of "immune contexture" and to the development of the Immunoscore, a standardized scoring system based on the density of two lymphocyte populations (CD3 and CD8) in the tumor core and at its invasive margin. This tool, whose prognostic value is highly significant, has been incorporated into the WHO classification of digestive tumors and into European clinical guidelines. Depending on the balance between tumor escape and immune coordination, colorectal tumors fall into three main profiles—hot, altered, and cold—with the altered profile further subdivided into "excluded" forms (in which T-cell infiltration is physically hindered) and "immunosuppressed" forms (characterized by suppressive cells, receptors, and soluble factors).
Understanding the mechanisms that give rise to these different profiles is essential for designing effective anticancer therapies. The authors carried out a comprehensive analysis of the entire set of cytokines and their receptors, combining comparative genomic hybridization, systems biology approaches, and large-scale analyses of the intratumoral immune response. This approach made it possible to identify the chromosomal alterations of cytokine genes associated with tumor progression, lymph node invasion, and distant metastases. Within the tumor microenvironment, interleukin-15 (IL-15) was found to be produced by epithelial cells and activated myeloid cells. The work shows for the first time that copy number variation of the IL15 gene determines immune cell densities in tumor regions.
Two complementary mechanisms thus shape the immune contexture. On the one hand, specific chemokines and adhesion molecules attract effector T lymphocytes to the tumor microenvironment and to certain precise regions of the tumor: CX3CL1 mainly recruits activated TH1 and cytotoxic lymphocytes, whereas CXCL9 and CXCL10 primarily attract CD45RO memory T lymphocytes. On the other hand, IL-15 drives in situ lymphocyte proliferation, expanding the local pool of cytotoxic CD8 T lymphocytes, as well as B lymphocytes. Actively proliferating lymphocytes correlate with patient survival: increased IL-15 expression and high local T-cell proliferation are associated with a reduced risk of recurrence and prolonged survival. These data, which shed light on the dynamics of tumor progression and recurrence, can help guide research priorities and the design of therapeutic interventions.