For centuries, physicians observed that celibate nuns had much higher rates of breast cancer, leading to the theory that pregnancy, childbirth, and breastfeeding might be associated with lower breast cancer risk. Numerous epidemiological studies have since supported this, finding that women with more children and who breastfed tend to have lower rates of breast cancer and other reproductive issues.
Over several decades, researchers’ explanation for this protection was a modest matter of hormones, and that by being pregnant and breastfeeding, mothers were essentially hitting “pause” on the hormonal fluctuations that influence cancer risk. Furthermore, by stopping ovulation, one can reduce the lifetime exposure to estrogen, the fuel that many cancers use to grow.
In addition, another intriguing theory was put forth: the “great rebuild.” Think of the breast during pregnancy and lactational processes as a structure undergoing a thorough renovation. The mammary gland grows to produce milk and then shrinks back down, whereby it undergoes a massive tissue remodelling.
It is believed that during this “reconstruction phase,” the old, tired cells—the ones most vulnerable to becoming cancerous cells—were simply cleared and replenished by stronger and newer reprogrammed breast epithelial cells. But as we’re starting to find out, there are more nuanced changes that occur during this lactation process.
Investigating a possible immune response
We began to wonder: What if this “great rebuild” wasn’t just about hormones or new cells? What if it were also about the origin of the specialized local immune response?
Think about the sheer biological orchestration of pregnancy and breastfeeding. The breast undergoes an extensive tissue remodelling, calling in an army of immune cells to clear out old cells and to build new ones. At the same time, evolution has engineered a magnificent, two-way dialogue of protection: When an infant is exposed to a germ, the mother’s body senses it through breastfeeding and produces the exact antibodies and immunity that the child needs.
This advancement of immune networks is an evolutionary masterpiece, designed to keep both mother and baby alive and thriving. Think of it as “nature and nurture.”
To this end, we asked the big question: Could this ancient, evolutionary mechanism of “immune surveillance” built for tissue remodelling and for nurturing the baby, be the very same thing that might also protect the mother from breast cancer decades later?
It turns out, yes—the maternal immune system has the capacity to form long-term memory that we have begun to unlock. In this study, we characterized the T cell landscape post-partum in detail, in cancerous and non-cancerous mammary tissue in both human and pre-clinical mouse models. Furthermore, we comprehensively evaluated the more complex immune system, including conventional Type I dendritic cells that play a key role in early cancer recognition, in addition to the ones that establish barrier immunity, such as in the skin and the lungs.
These T cells are unique because they have something incredible called “memory potential.” They don’t just put out a fire and leave; they remember any local tissue anomalies that were processed, including any invaders. They stay in the tissue for decades, programmed to recognise a threat they’ve seen before, and we know from our previous studies that memory CD8+ T cells hunt down tumours and cancer-proof the tissue.
Memory T cells as a cancer defence?
The big question we asked was: Does the body use this powerful resource, i.e., memory T cells, to build a long-lasting defense against breast cancer?
To experimentally prove this, we took two groups of mice. One had gone through pregnancy and lactation, the other did not. First, we verified our initial human findings: just as in women, the parous mice had a huge surge of memory CD8+ T cells.
In the mice that had been pregnant and undergone a full course of lactation, the tumours grew significantly slower, suggesting that the protective immune micro-environment was very efficient. We recognized we were onto identifying the key immune population. At this juncture, we isolated the key variable, i.e., CD8+ T cells, and repeated the experiments in multiple preclinical models.
This time, in one group of mice, we specifically destroyed the CD8+ T cells—our prime gladiators. And to our astonishment, the mammary tumour protection vanished. This indicated that without the T cells, the tumours grew unchecked. This definitively proved the tissue protective role of memory CD8+ T cells postpartum by reshaping the body’s natural defences that shield from breast cancer growth.
Contemporaneously, when we looked at our large human dataset, a clear pattern emerged. One that indicated that the longer the duration of breastfeeding, the stronger the shield becomes, with more T cells in the breast with the potential to recognize and react to cancer at early stages.
To this end, statistical evidence suggests a reduction in breast cancer risk of about 4% for every 12 months of cumulative breastfeeding. With every child, the breast becomes more efficient at clearing away debris, rebuilding itself by recognizing tissue threats. Crucially, we believe this extended time assists in “anchoring those vital memory CD8+ T cells, creating a permanent base within the mammary tissue where they grant the first line of immunological defence against breast cancer.
While breast cancer risk temporarily rises during pregnancy and early postpartum, here we demonstrated long-term protection (>5–10 years postpartum) through the development of a “breast immune shield” made up of CD8+ T cells. Our work also forms the basis for using the immune system to treat cancer and further utilize it for cancer prevention strategies.
We acknowledge that breastfeeding isn’t always an option for everyone and offers no guarantees for every woman in terms of protection against a complex disease driven by many factors. Our study ultimately focused on decoding the natural protective mechanisms, a breakthrough that may transcend the frontier of cancer medicine and translate tissue protective immunity to all women regardless of reproductive history.
Source: Nature
