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As we have written about before, cancer immunotherapy aims to make use of the body’s own immune cells to attack cancer cells, thereby preventing their continued growth. However, the body has a system of checks and balances in place to make sure that the immune system does not accidentally attack healthy tissue. These checks and balances are required to prevent the development of autoimmunity. However, they also stand in the way of enabling a full-scale immune response to cancer cells, which closely resemble healthy cells, as cancer cells arise from normal tissue that acquires damage. In 2018, the Nobel Peace prize in medicine was awarded to James Allison and Tasuku Honjo for their work on the development of ways to temporarily disable key “checkpoint” regulators, allowing the immune system to attack cancer cells more efficiently. The approach of using “checkpoint inhibitors” to enhance the immune response against tumors has led to improved therapy for a number of types of cancer.
However, cancer immunotherapy with checkpoint inhibitors is only effective in roughly 10-30% of patients, and only in certain types of cancer. In a paper published in April 2019, Poggio et al. discovered one possible strategy that cancer cells use to further disable the immune system, allowing them to evade therapy with immune checkpoint inhibitors. Usually, checkpoint inhibitors bind to the checkpoint molecules that are expressed directly on the surface of tumor cells. This blockade then enables your immune cells to attack the cancer cells. However, Poggio et al. discovered that the tumor cell surface is not the only place where the immune-deactivating checkpoint molecules are expressed.
The focus of this paper was on how tumor cells send out “messages in a bottle” – small blebs of cell membrane loaded with immune checkpoint molecules and other proteins, lipids, and sugars – out away from themselves. These small vesicles are called “exosomes,” a term that is derived from “exo,” meaning outside of, and “some” which is a variant of “soma” which means the body (the “body” being the lipid particle, in this case). Put together, exosomes are small external “bodies” that leave the cell to carry messages to other cells in the body.
Because these cancer-derived exosomes are coated with inhibitory proteins, they can disable immune cells that are not in close proximity to the tumors themselves. Confusingly, these small exosomes are not efficiently suppressed by the checkpoint inhibitor therapies, despite having the same immunosuppressive molecules on their surface. Poggio et al. have hypothesized that this may be due to the expression of slightly different variants of PD-L1 on the surface of exosomes. Or, perhaps the exosomal expression of PD-L1 is too high to be totally covered by a dose of checkpoint inhibitors. The researchers believe that it is this distinction that allows tumor-derived exosomes containing checkpoint molecules to turn off the immune system even in the context of therapy with checkpoint inhibitors.
A recent study of ovarian cancer cells found that a more invasive cancer cell line released more exosomes than a less invasive sample. Significant research in recent years has focused on cancer-based exosomes as a possible strategy for detection of cancer. Exosomes can be collected from blood, plasma, urine, and saliva, and they can carry various types of cargo, including proteins, lipids, and microRNA (small gene fragments that can suppress the production of specific molecules in other cells). A 2014 study of the microRNA contents of exosomes isolated from the blood of patients with colon cancer identified some microRNAs that were much more common in colorectal cancer patients than healthy controls, suggesting their potential use as a screening tool. Importantly, the levels of those intra-exosomal microRNAs were also significantly elevated in patients with early-stage disease.
There are ongoing efforts to understand the roles that exosomes play in remodeling the blood supply to tumors, influencing the environment directly around the tumor, and influencing distant elements of the immune system. Each of these research directions could open the door to new therapeutic approaches focused on limiting the pro-tumor activity of the exosomes that are released by cancer cells. Further, differences in the specific characteristics of exosomes found in the blood of patients with cancer could lead to minimally invasive and cost-effective methods for early screening of disease.
Poggio, M., Hu, T., Pai, C. C., Chu, B., Belair, C. D., Chang, A., . . . Blelloch, R. (2019). Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory. Cell, 177(2), 414-427 e413. doi: 10.1016/j.cell.2019.02.016