Sensing hyperploidy and immune surveillance: a pas-de-deux.

The immune surveillance hypothesis posits that tumor cells are subject to control by the immune system based on the recognition by T cells of tumor-associated antigens presented in the context of major histocompatibility complex (MHC) molecules. Operationally, this requires phagocytosis of tumor cells by host antigen presenting cells, such as macrophages and dendritic cells, which leads to the generation of tumor antigen-specific T cells, thus promoting the elimination of tumor cells. Mechanisms by which tumor cells evoke attention from immune cells are not fully understood.

In this issue, Boilève et al. suggest that hyperploid colon cancer cells are subject to “hardwired” immune surveillance that results in immunological control of hyperploid neoplastic cells. They use a system of transformed colon cell organoids, in which the tumor suppressor gene Tp53 is silenced to facilitate hyperploidization. Interestingly, while wild-type colon cancer cells are not readily inducible to tetraploidy, Tp53 silencing renders them responsive to pharmacologically induced hyperploidy as well as spontaneous hyperploidization, consistent with previous data demonstrating that Tp53 control of the G1 checkpoint is a barrier to pharmacologically induced hyperploidization. Hyperploid Tp53 colonocytes initially grow in syngeneic immunocompetent hosts but fail to progress. Histologically, these tumors are fibrotic and display chaotic cellular architecture. Conversely, hyperploid Tp53 colon cancer cells grow progressively in immunodeficient hosts and form organized structures. Additionally, the nuclei of graft cells in immunodeficient mice are larger than those of cells growing in immunocompetent mice, implying increased ploidy. Taken together, these results suggest that the immune system senses hyperploid colonocytes and, in turn, controls their growth.

Investigating how tetraploid tumor cells are sensed by the immune system, the authors show that Tp53 tetraploid colonocytes heterogeneously upregulate cell surface expression of calreticulin, which is trafficked to the cell membrane during apoptosis serving as an “eat-me” signal for macrophages and dendritic cells. They additionally show that hyperploid Tp53 colonocytes in immunodeficient mice express the phosphorylated form of eukaryotic initiation factor (eIF) 2α, suggesting that these cells undergo ER stress response. Recently the same group showed that an intact ER stress response is necessary for calreticulin upregulation in hyperploid cancer cells. Thus, the increased immunogenicity of hyperploid neoplastic cells is driven by an ER stress response-mediated upregulation of calreticulin, leading to increased uptake of hyperploid cells by phagocytes, and initiation of a specific cellular immune response. The nature of the immune response against hyperploid transformed cells should be the subject of future study.

Why does increased uptake of hyperploid cancer cells lead to their selective elimination? While increased protein content in a hyperploid cancer cell would ostensibly lead to greater quantitative presentation of antigens to T cells, this alone would not necessarily lead to selective elimination of hyperploid cancer cells. Rather, one would expect the elimination of all tumor cells presenting the same antigen, including diploid cancer cells. An intriguing possibility is that hyperploidization of cancer cells changes their antigenic repertoire, driving the expansion of T cells specific for hyperploidy-associated antigen(s). Alternatively, hyperploid cancer cells may be simply “better” targets than neighboring diploid cancer cells for cytotoxic T cells due to increased cell-surface display of antigen, even though target recognition and killing by cytotoxic T cells was shown to require as little as a single MHC-antigen complex.

The role of the ER stress response in the tumor microenvironment remains an open question. Boilève et al., as well as previous work from the same group, suggests that the ER stress response enforces expression of calreticulin on hyperploid cells, thus promoting tumor immune surveillance. On the other hand, others have shown that the ER stress response is a cell-intrinsic survival mechanism for cancer cells. Further supporting a tumorigenic role for the ER stress response, recent work has uncovered a novel cell-extrinsic role for the tumor ER stress response in polarizing myeloid cells to a pro-inflammatory/suppressive phenotype that impairs CD8+ T cell priming and facilitates tumor growth in vivo. Reconciling these seemingly contrasting effects, we suggest that the tumor ER stress response may fulfill both functions, perhaps promoting cellular immunity against hyperploid cells while simultaneously undermining the immune response against cancer cells. The fact that clinical tumors samples exhibit heterogeneous ploidy suggests that this might indeed be the case.