The Immune System & Cancer

Cancer is controlled by chemotherapy or radiotherapy, but not cured by either. It is the immune system — or rather the cells of the immune system, alone or in unison — which eliminate the last tumour cell.

We all have an immune system, yet some of us develop cancer. The answer to this paradox lies in understanding how immune surveillance works, how it can fail, and how modern therapy is built around restoring or replacing it.

The immune system maintains its surveillance 24×7 to protect us from cancer as well as infectious pathogens. The sentries of the immune system — macrophages and the family, T cells and NK cells — in tandem hunt down any cell that tends to show signs of turning rogue.

Each cell of our body is under a very refined system of central and local control. Cells do their job and then perish, or switch off their sensor for growth. These immune sentries sense the earliest signs of a cell failing to switch off the sensor and going out of the control mechanism. They are nipped in the bud.

In some of us, these sentries fail to execute their job in time. This is either because they have been tired, tricked, tamed or told off by the potential cancer cells. This can be due to a serious infection or repeated infections, genetic mutations, or prolonged intake of drugs which dampen the immune cells. Under these conditions, one such rogue cell rapidly multiplies and overwhelms the immune system. Once outnumbered, the immune sentries — even if they try desperately — fail to control the cancer cells.

That is where the role of chemotherapy or radiotherapy comes in. They kill the cancer cells like a head-to-head battle in the open. In the process, they often damage normal cells — mostly blood cells, but also various tissues. However, this is essential as there is no other way to curb this uncontrolled growth of the rogue cells. In solid organ cancers, cutting off the affected tissue in part or whole is the standard approach if possible. Otherwise, it is deemed incurable.

The importance of the immune system in controlling and eradicating cancer cells in blood cancers has been recognised since the 1980s. This was largely due to the successful introduction of Allogeneic BMT — replacing the recipient's bone marrow stem cells with healthy ones from a donor, following high doses of chemotherapy and/or radiotherapy. This resulted in cure in patients with relapsed and resistant leukemia.

In the first decade after its introduction, the cure was believed to be due to high doses of chemotherapy or radiotherapy. However, it was also observed that the same procedure carried out with the patient's own stem cells (Autologous BMT) resulted in higher relapse rates — i.e., less chance of curing the leukemia. In addition, when donor cells caused severe reaction against the patient's organs (Graft-versus-Host Disease, GVHD), the chance of eradicating the leukemia increased. Furthermore, transfusing white blood cells from the donor (Donor Lymphocyte Infusion, DLI) was found to cure some blood cancers relapsing after an Allogeneic BMT.

These observations led to the development of the concept of the Graft-versus-Leukemia effect of Allogeneic BMT — a paradigm shift in our understanding of how cancer is cured.

In the last decade, this concept has seeped into the field of solid tumours, where the reliance has been on surgery and chemo-radiotherapy. Tasuko Honjo and James Allison discovered a couple of unique proteins which keep the immune system under check. It was observed that in certain solid tumours like melanoma, blocking these proteins resulted in rejuvenation of T cells and regression of the tumour. This approach has now been extended to almost all solid tumours, with some showing excellent response to inhibition of immune checkpoint inhibitors.

Thus, the tectonic shift in our understanding and treatment of cancers has put the immune system and its manipulations at the forefront.