Some Information on Immunotherapy and Gliobalstoma

Waiting for the next issue on the news of research in this two-month period and considering that we always hear often about immunotherapy, vaccines and many of the new trials that are trying this approach, I decided to respond to the request of all those who ask me to provide some information on the subject in order to better understand how it works. We also know that in general in glioblastoma it is considered a cold tumor and therefore many of the approaches on immunotherapy tested so far have not led to significant results. Results are now being obtained using combined approaches that aim to transform glioblastoma from cold tumor to hot tumor and therefore more suitable for this approach.

Now as you know I am not an expert and therefore I will be happy to receive comments aimed at clarifying and perfecting any of my inaccuracies.

Lymphocytes (B cells, T cells) belong to the adaptive arm of the immune system. The rest of the immune cells belong to the innate arm.

Cytotoxic T cells (CTLs) kill damaged and abnormal cells, while B cells produce antibodies that bind to their targets such as cells, viruses, bacteria and foreign proteins. Antibodies bound to their targets induce target elimination. Both types of lymphocytes are very important. Antibodies attack foreign particles such as viruses directly, whereas T cells can eliminate only other cells such as cancer cells or infected cells, but cannot directly attack viruses or bacteria or foreign proteins.

Macrophages and dendritic cells are members of the innate arm. They are the first responders, they swallow foreign particles and digest them. They make small pieces of foreign particles called antigens visible to the other cells of the immune system. Antigen presentation occurs in the lymph nodes.

B and T cells have BCR and TCR receptors, respectively. B and T cells waiting in the lymph nodes for antigen presentation. Each B and T cell has unique BCRs or TCRs on the surface that allow it to recognize particular (cognate) antigens.

Those B and T lymphocytes that find related antigens are activated. They leave the lymph nodes and circulate in the blood to find cells that look like these antigens. When a T cell finds cancer cells displaying its cognant antigen it proliferates to make an army of such T cells and they all attack the tumor.

Tumors and in particular glioblastoma respond to this threats. They express markers that inactivate cytotoxic T lymphocytes. New immunotherapy drugs try to prevent inactivation.

The most important marker of T lymphocytes is PD-1. It’s just a protein molecule from the immunoglobulin superfamily. When a cytotoxic T cell kills dozens of cancer cells, it expresses the PD-1 marker. This marker means that the T cell is activated and that it is exhausted. It can no longer kill cells. This is a mechanism to keep T cells under control. Otherwise they could kill many more cells. But the tumor reacts. It causes the expression of PD-L1 which is the ligand of PD-1. The ligand binds to PD-1 and inactivates the T cell. Drugs such as Keytruda remove the ligand from PD-1. The activity of T lymphocytes is then restored, which can thus continue to kill cancer cells.

Now why immunotherapy doesn’t work for many cancers like glioblastoma? The reason lies in the microenvironment that glioblastoma cells create around them.

In general if the cancer cells are not very different from normal cells, the immune system is unable to recognize them. The more mutations in a cancer cell, which makes it different from a normal cell, the better the immune response. We want the cytotoxic T cells to recognize the tumor and infiltrate it and start killing the tumor cells and when the tumor expresses PD-L1 we will use systems that allow immunotherapy to reactivate the cytotoxic T cells.

I hope I have provided some useful information in this short note. Clearly the advantage of the result of immunotherapy lies in its naturalness, in its focus on target cells which in general has the consequence of not producing the side effects of traditional chemotherapy.