IL15 deletion in colorectal cancer is associated with reduced lymphocyte proliferation and poor outcome.

  • Major finding:IL15 deletion in colorectal cancer is associated with reduced lymphocyte proliferation and poor outcome.

  • Concept: Secretion of IL15 by tumors may promote the infiltration of immune cells with antitumor activity.

  • Impact: IL15 may be a prognostic biomarker in colorectal cancer as well as a potential therapeutic target.

Immune cell infiltration has been shown to be a predictive biomarker in colorectal cancer, with high densities of infiltrating T and B cells in the tumor microenvironment associated with favorable prognosis. Given that cytokines are powerful modulators of antitumor immune responses, Mlecnik and colleagues evaluated cytokine and cytokine receptor gene copy number variations in 109 colorectal cancers to identify any that correlated with clinical outcome and thus possibly contribute to immune reactions in colorectal cancer. More than 75% of tumors did not harbor cytokine genomic alterations, but approximately 20% had alterations affecting the interleukin family, with the highest magnitude of loss observed for interleukin 15 (IL15). Metastatic tumors harbored significantly more deletions in interleukins, including IL15. IL15 deletion led to a significant reduction in IL15 expression and was the only deleted gene that was associated with a higher risk of relapse, suggesting that IL15 may normally contribute to antitumor immune responses in colorectal cancer. Consistent with this possibility, tissue from colorectal tumors with IL15 deletion had fewer proliferating T cells present compared with tumors in which IL15 was not deleted, and IL15 induced the proliferation of T cells isolated from colorectal tumors ex vivo. Moreover, an independent cohort of tumors with high IL15 expression showed a higher density of proliferating lymphocytes both at the invasive margin of tumors and within the tumor center than tumors with low IL15 expression. High IL15 expression was also associated with a lower risk of relapse, providing further evidence that activation of T cells by IL15 might lead to more effective antitumor responses. In addition to implicating IL15 deletion as a potential mechanism of immune escape in colorectal cancer, these findings suggest that IL15 deletion may have utility as a prognostic biomarker in colorectal cancer and that IL15 may be a useful immunotherapeutic agent.

Mlecnik B, Bindea G, Angell HK, Sasso MS, Obenauf AC, Fredriksen T, et al. Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients. Sci Transl Med 2014;6:228ra37.