In Aging Cell, researchers have published the surprising and counterintuitive finding that older immune cells are able to kill cancer cells more quickly than their younger counterparts.
The aging of CD8+ T cells
The researchers introduce their subject by discussing CD8+ T cells in the context of aging. These cells form a major part of the immune response; when presented with an antigen, they rapidly divide and differentiate into multiple types, notably central memory and effector memory cells [1]. These cells are heterogenous and highly complex, and they are known to deteriorate with age in multiple ways: they fail to proliferate as much [2], the way they produce inflammatory cytokines changes [3], and the populations of memory cells into which they proliferate change as well [4].
Bizarrely, though, previous research has shown that older CD8+ T cells are more effective in fighting cancer than younger ones [5]. This research took a deeper look into this discovery, using cells from one cohort of 12- to 24-week-old female mice and another cohort of 78- to 102-week-old mice to investigate why this is the case.
Quicker to begin their work
In the absence of activation, CD8+ cells from both younger and older mice did not effectively attack P815 tumor cells in vitro. Cells from older mice appeared to be slightly more effective, but the difference was not statistically significant.
When chemically activated, however, there was a clear difference in their immediate effectiveness against P815 cells. One hour after activation, older CD8+ T cells had killed thrice the cancer cells than their younger counterparts. At the three-hour mark, the younger cells had finally caught up, being slightly more effective four hours into the experiment. Testing against a different tumor line, EL4, yielded similar results except that the older cells were slightly, but not significantly, more effective four hours later.
Ruling out explanations
The researchers then tested whether or not the regulatory cytokine IL-2 was responsible for any of these effects. This was not the case: increasing IL-2 had positive effects on the younger cells, making them more able to kill more cancer cells in the end, but it did little to speed up their activities; older cells were barely affected at all.
As aging affects the populations of central and effector memory cells, the researchers then tested to determine if these subtypes were responsible. This was also found not to be the case: the curves of both types of cells were very similar, and older cells had the rapid response that the younger cells did not.
Time-to-contact was also not responsible for this. Microscopic examination showed that younger cells were able to find cancer cells at almost exactly the same rate as their older counterparts. They simply did not begin destroying the cells as quickly.
A close look at the cellular weapons
CD8+ T cells contain granules full of compounds that are deadly to cells (cytotoxins), with one of the most notable being granzyme B. To kill cancer cells, these immune cells open these granules, and in the process, one of the released proteins is particularly easy for researchers to detect. However, these researchers found no differences between older and younger cells in their rates of degranulation.
There were differences, however, in the contents of these granules. Older cells had more granzyme B and engaged in more granule fusion, suggesting that their contents were more deadly to cancer cells. Further investigation showed that this difference in content was substantial: activated CD8+ T cells from older animals have five times the gene expression of granzyme B and almost 20 times the expressions of granzyme A and perforin, a compound that causes target cells’ membranes to rupture.
Conclusion
The authors of this paper show a simple and easy-to-understand reason for older T cells’ rapid effectiveness against cancer cells: they have stronger weapons on hand with which to kill them. However, as the authors readily admit, they do not know why this is the case, particularly in light of older cells’ weaknesses in many other areas, such as against non-cancerous pathogens. A substantial amount of investigation will need to be done in order to understand how and why older cells excel in this particular area even while deterioriating in many other ways.
Literature
[1] Williams, M. A., & Bevan, M. J. (2007). Effector and memory CTL differentiation. Annual review of immunology, 25(1), 171-192.
[2] Jiang, J., Fisher, E. M., & Murasko, D. M. (2013). Intrinsic defects in CD8 T cells with aging contribute to impaired primary antiviral responses. Experimental gerontology, 48(6), 579-586.
[3] Mirza, N., Pollock, K., Hoelzinger, D. B., Dominguez, A. L., & Lustgarten, J. (2011). Comparative kinetic analyses of gene profiles of naive CD4+ and CD8+ T cells from young and old animals reveal novel age‐related alterations. Aging cell, 10(5), 853-867.
[4] Goronzy, J. J., & Weyand, C. M. (2017). Successful and maladaptive T cell aging. Immunity, 46(3), 364-378.
[5] Saxena, R. K., & Adler, W. H. (1999). Cytolytic activity of mitogen activated old and young mouse spleen cells against tumor target cells expressing high or low levels of Fas antigen. Experimental & Molecular Medicine, 31(3), 137-141.
