You might think of cancer as a mass of rogue cells that grow uncontrollably. But cancer is more organized and strategic than that. Rather, cancer is a tightly controlled cellular neighborhood that can keep the body’s defenses out or weaken them once they get in.
Cancer behaves like a gated community. It has its own residents, rules and security systems. Together, these features create what scientists refer to as the tumor microenvironment, where cancer cells live and interact with the body. To devise new treatments that can break into this neighborhood, researchers are learning how cancer builds its own roadways and places improvised explosive devices to destroy any unwanted guests, including anticancer drugs.
We are cancer researchers studying how tumors evade the immune system and weaken the effectiveness of treatments meant to destroy them. We devised a way to add a protective shield over anticancer immune cells, allowing them to enter cancer’s neighborhood unscathed and decapitate tumors.
What is the tumor microenvironment?
Cancers don’t just passively exist in the body. They create an ecosystem of other cells and components that actively controls what gets in, what they can do and how long they last.
This ecosystem provides a highly coordinated and supportive infrastruture for a cancer to live in. The cancer instructs the body to build super roadways (blood vessels) and homes (tumor cells) resistant to decay.
It also installs security devices (protective molecules) to eliminate unwanted guests and enlists loyal law enforcement officers (other cells in the body) by releasing recruitment signals (molecules called cytokines and growth factors) to the normal tissues surrounding it.
The tumor microenvironment allows cancer to withstand an onslaught from a body’s natural immune defenses. It also allows tumors to escape what would normally be catastrophic changes in temperature and oxygen levels.
How well cancer coordinates the construction and maintenance of this neighborhood is constantly in flux. This give cancer researchers opportunities to disrupt the tumor’s ecosystem and attack it.
Engineering immune cells to kill cancer
The tumor microenvironment poses a major problem for the immune system’s ability to recognize and destroy abnormal cells, including cancer.
Cancer cells often find ways to avoid detection or suppress immune responses. One way they do this is by altering the sugars that cover their surfaces. Normally this sugar coat triggers the immune system to kill the cancer cells. But tumors can change these sugars in a way that make them no longer recognizable to the immune system. Additionally, cancer cells can secrete molecules that can deactivate the ability of immune cells to kill them.
To overcome the tumor microenvironment, researchers have developed a treatment called chimeric antigen receptor T cell therapy, known as CAR-T therapy for short. In this approach, a patient’s T cells – a type of immune cell that fights pathogens and cancer – are removed and genetically engineered to better recognize cancer before being returned to the body.
National Cancer Institute (NCI)
You can think of these engineered cells as highly trained fighters with the ability to identify cancer cells through the equivalent of specialized night vision goggles and training on how to recognize the headquarters of cancer cells.
CAR-T therapy has been highly effective in some blood cancers, particularly when the tumor microenvironment or bloodstream is shared by both normal immune cells and blood cancer cells. But it has faced difficulty treating solid tumors because the tumor microenvironment has been a major obstacle for T cells to gain entry.
Molecular improvised explosive devices
But entering the cancer is only part of the challenge. Once inside, CAR-T cells encounter a hostile tumor environment filled with molecules that can weaken or disable them.
Some of these molecules act like roadblocks, slowing immune cells down. Others behave like misleading traffic signs, sending confusing instructions. Some can attach to CAR-T cells and disrupt their ability to wield their weapon and attack the cancer cells. In many cases, the cancer deprives CAR-T cells of the energy they need by designing a tortuous roadway to get into their neighborhood.
One key molecule involved in blocking CAR-T cells is called galectin-3. Cancers can release this protein into the tumor microenvironment, where the molecule attaches to the T cells and change their ability to communicate with other cells, confusing the T cells and restricting their ability to survive and kill cancer.
The tumor microenvironmnt is one reason why CAR-T therapy, while powerful, does not always lead to long-lasting responses. The cells may reach the gate and enter the tumor, but they don’t always remain functional long enough in the neighborhood to eliminate cancer cells.
Protecting CAR-T cells in tumors
How can researchers help CAR-T cells survive the tumor microenvironment? One way is to protect the outer sugar coat of CAR-T cells and prevent galectin-3 from binding to it.
Our team has developed a way to instruct CAR-T cells to make a new sugar coat that can ward off galectin-3. This concept of targeting sugar molecules in drug development is called glycoengineering.
Every cell in the body is coated with sugar molecules called glycans. You can think of it as a coat that cells can change depending on the environment. These sugars play an important role in controlling how cells interact with their surroundings. CAR-T cells have a peculiarly sticky sugar coat that makes them particularly vulnerable to molecules like galectin-3.
Mantuano et al/Journal for ImmunoTherapy of Cancer, CC BY-NC-SA
Our team genetically modified the sugar layer on CAR-T cells to change how they behave in the tumor microenvironment. We added genes into CAR-T cells that change the types of sugars they produce for their coats, better camouflaging them against galactin-3.
Because glycoengineered CAR-T cells can better resist galectin-3’s ability to shut down their cancer killing, they can maintain their function longer and communicate with each other better in the tumor microenvironment. This longer, more persistent form of CAR-T cell therapy can help prevent tumors from developing resistance against them.
Resilience over brute strength
While researchers still don’t completely understand how tumors regulate their neighborhoods and restrict immune cells from coming in, addressing these weaknesses points to future solutions for cancer.
Instead of making immune cells more powerful, scientists are seeking ways to make them more resilient. Helping immune cells adapt to cancer’s ecosystem could extend their effectiveness and improve patient outcomes.
Glycoengineering also reflects a broader shift in cancer research. The focus is no longer just on attacking cancer cells directly, but also navigating the tumor microenvironment in order to protect immune cells in their mission to kill cancer cells.
In the future, we believe the most effective cancer treatments may not be the strongest, but the ones best equipped to operate within the gated community that tumors create.
