Cancer is smarter than we are. In fact, cancer is winning the war. While the incidence of cancer has fallen over the last decade, it still affects one in three people, is a frequent cause of death, and is a major contributor to overall healthcare costs. The first question we need to ask is why we get cancer in the first place. While there is not one answer, at its most basic level cancer is a disease of aging. The risk of cancer increases with each decade of life until you reach the late 60s when the risk of developing cancer begins to decline. But on a fundamental level, the development of cancer is a failure of the immune system.

The immune system has evolved to protect us from disease. In most people, Natural Killer (NK) cells of the innate immune system serve as the body’s police force, patrolling for abnormal cells that will become cancer and eliminating them before they develop further. The truth is that our bodies produce millions of “suspicious” cells every day – NK cells eliminate them before they cause problems. If only the story ended there. Unfortunately, it is only the beginning.

Cancer has one job—to survive. In order to do so, it must evade elimination from the patient’s immune system. One way it does this is by down-regulating surface receptors which typically alert NK cells to its cancer-like properties. Without these signals, NK cells ignore the cancer cells assuming they are harmless, allowing them to thrive so they grow into a mass that becomes a malignant tumor. Many do not realize it takes a decade for that sentinel cancer cell to grow into a tumor that is clinically relevant. What is the immune system doing during all that time? Nothing—it ignores the cancer and the cancer grows! The immune system does not lose its ability to kill cancer cells; it loses its desire to kill them. That is, NK cells have the necessary ammunition to kill cancer cells, but they choose not to use their arsenal because they do not identify the malignant cells as abnormal.

Once the cancer is established an even more dastardly immune evasion system kicks in—the cancer subverts the patient’s immune system into protecting it. Immune cells that are supposed to be protecting the patient by killing the cancer cells, are “repurposed” into cells that protect the cancer from being killed by the patient’s immune system. These traitorous cells are present in the tumor microenvironment (TME) at a very early stage. In many tumors, there are more immune cells than cancer cells. Unfortunately, these cells are protecting the tumor from the patient’s immune system and anticancer immunotherapies, instead of attacking it. The traitors! What nerve!

Biologically, this immunologic repurposing is an elegant process. I call these subverted cells “protector cells.” Before the cancer convinced them to switch sides, these cells were patrolling the body looking to eliminate infectious agents and abnormal cells. However, the cancer converts them into “protectors” that produce an immunosuppressive environment that enables the tumor to thrive while actively preventing cancer killing cells from attacking the growing malignancy. These primary cancer killing cells are NK and T cells, which I call “effector cells.” In the setting of cancer, the effector cells are responsible for the actual killing of each cancer cell. This killing is up-close and personal, requiring cell-to-cell contact with each cancer cell. The immunologic battle line has been drawn—it is a battle between the effector and the protector cells. The outcome is literally life or death. If the effectors dominate, the patient lives. If the protectors win…

The players in the game

Protector cells are an alphabet soup of immune cells that populate the TME including MDSC (myeloid derived suppressor cells), TAM (tumor activated macrophages), CAF (cancer associated fibroblasts), Treg (T regulatory cells), and TAN (tumor activated neutrophils). Each of these cells nurture the tumor, encourage growth, and potentiate malignancy to become more invasive by encouraging both epithelial mesenchymal transformation and migration as metastasis. MDSC, TAM, and Treg secrete immunosuppressive cytokines that neutralize effector cells attempting to attack the tumor. Unlike MDSC and TAMs, only Tregs exist in patients without cancer. By definition, if you have cancer and your cancer is growing, you have MDSC, TAMs, and unfortunately, the protectors are winning the war.

Fully functional effector cells are essential in this fight for survival. Most of the heavy lifting is done by NK cells and CD8+ cytotoxic T cells which attack and infiltrate the TME to kill the cancer cells. That is, they are supposed to attack and infiltrate the TME and kill cancer cells, but in patients with cancer, they do not. Often, effector cells sit outside the TME, fiddling while Rome burns! The effector cells cannot gain entry into the TME due to the immunosuppressive force field surrounding the tumor, and if they do succeed in infiltrating the TME, they are bathed in the immunosuppressive cytokine soup secreted by protector cells that renders them lethargic and inactive.

Immunotherapy: Bringing effector cells into the fight

Until recently, the cancer and its posse of protector cells had the upper hand. However, new developments in cancer therapy are changing the dynamics of the fight. The primary goal of modern immunotherapy is to improve the ability of effector cells to attack developing cancer cells. More specifically, monoclonal and poly-functional antibodies and immune checkpoint inhibitors (CPI) have a single strategy—improve the ability of effector cells to kill the cancer. A stronger effector cell is a better effector cell.

But it is not so simple. Protector cells still blunt the ability of these newly energized effector cells. For instance, if the tumor does not have tumor infiltrating lymphocytes (TIL), then CPI will not work because there are no effector cells in the tumor. This is called a “cold” tumor—an effector cell desert where no amount of CPI will make the tumor respond to the therapy. But even if the tumor has TIL, they cannot do their job of killing the tumor because the immunosuppressive cytokines secreted by the protector cells which sedate, paralyze, and otherwise neutralize effector cells, allow the tumor to thrive. In this case, the tumor is “hot,” with abundant TIL but still needs an immunologic boost from a CPI so the effector cells will attack the cancer.

Expanding our arsenal: Making cold tumors hot

In my opinion, the clinical community and biotech companies have shown little imagination in solving the problem of the immunosuppressive TME. To date, therapeutic development has focused on improving effector cells, highlighting the bias that improving effector cell function will solve the problem. Experience has shown us that this is a solution in only a minority of patients. Two-thirds of patients receiving CPI do not respond to this effector cell stimulation. To combat the low response rates of effector-targeted therapies, many clinicians and biotech companies have decided that the best approach to primary or secondary immunotherapy resistance is brute force. If one CPI does not work, use two! Predictably, the benefit of two CPI is marginal and the toxicity has been problematic.

I propose a different approach to this problem. If the single effector strategy fails, add a therapy that targets protector cells. If you eliminate the protectors, the effector will become… effective. That is, target MDSC or Treg to eliminate the potent immunosuppressive shield that prevents the effector cells from entering the TME in the first place. Doing so should turn cold tumors hot. This strategy combines complementary therapies that alone are not effective, turning them into a combination therapy that works. This is synergism’s finest hour! The future of effective immunotherapy will be protector-targeted therapies that are administered in combination with effector-targeted therapies. As the medical community shifts its approach, I am confident that the next frontier in cancer therapy will be protector-targeted therapies to boost immunotherapeutic patient response rates.

 

Raymond J. Tesi, MD, is CEO of INmune Bio, an immunotherapy company developing treatments to reprogram the innate immune system to fight disease.

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