Cell Transformation Triggers the Expansion of Cytotoxic Lymphocytes

The immune system has opposing roles in tumorigenesis: It can promote tumor development, via an inflammatory response, or suppress tumor development, via the continuous elimination of nascent tumor cells by antigen-specific lymphocytes in a process known as cancer immunosurveillance. However, it has been shown that while oncogene-driven tumors elicit tumor antigen–specific CD8⁺ T-cell responses, these responses do not result in host protection. To define the specific immune response elicited by oncogene-induced cancers, Dadi and colleagues characterized cytotoxic lymphocytes in transgenic models of murine mammary and prostate cancers. Examination of mice with early-stage tumors or age-matched wild-type mice identified the increased presence of lymphocytes expressing the cytolytic molecule granzyme B (Gzmb) in transformed tissues. Flow cytometric and gene expression analyses revealed the presence of two novel lineages of Gzmb-expressing lymphocytes in transformed tissues: unconventional type 1 innate lymphoid cells (ILC1I) and type 1 innate-like T cells (ILTC1), both of which were functionally similar to, but transcriptionally distinct from, conventional NK (cNK) cells. Both ILC1Is and ILTC1s were tissue-resident, selectively proliferated in tumors, and exhibited increased expression of genes involved in various cytotoxicity-inducing pathways such as the effector molecules Gzmc and TNF superfamily member 10 (Tnfsf10, which encodes for TRAIL). Consistent with these findings, deletion of perforin, a cytolytic mediator of the lytic granule pathway, in an autochthonous mouse mammary tumor model resulted in the reduction of cytotoxicity mediated by ILC1Is, ILTC1s, and cNK cells, and accelerated tumor growth. Overexpression of IL15 drove the expansion of ILC1Is and ILTC1s and reduced tumor growth in vivo. Together, these results show that oncogenic transformation provokes the expansion of lineages of unconventional tissue-resident cytotoxic lymphocytes, but not cNK cells, to drive cancer immunosurveillance.

Dadi S, Chhangawala S, Whitlock BM, Franklin RA, Luo CT, Oh SA, et al. Cancer immunosurveillance by tissue-resident innate lymphoid cells and innate-like T cells. Cell 2016;164:365–77.

• ©2016 American Association for Cancer Research.