A team led by surgeon-scientist Dr. Vinod Balachandran identified the molecular pathway involved in the formation of tertiary lymphoid structures. Therapeutically targeting this pathway could potentially enhance the immune response to cancer.
A research team at Memorial Sloan Kettering Cancer Center (MSK) has made new insights into how the body forms immune cell clusters called tertiary lymphoid structures (TLSs) in response to foreign threats such as cancer.
TLSs serve as the immune system’s on-site responders, forming in chronically inflamed tissues, including tumors, to bolster the local immune response. Understanding the molecular signals involved in triggering TLSs to form in tumors could lead to new immunotherapy treatments for cancer.
“Current immunotherapies don’t work for most cancer patients,” says Vinod Balachandran, MD, who led the research. Dr. Balachandran is a surgeon-scientist in the Human Oncology and Pathogenesis Program and Director of the Olayan Center for Cancer Vaccines (CCV) at MSK. “For such patients, new immunotherapies that unleash a more powerful attack against cancers are needed. Treatments that promote TLS formation may be able to accomplish this.”
In their latest study, published in Nature, the team used mouse models of pancreatic cancer to identify a new molecular pathway that leads to TLS formation. They also showed that therapeutically targeting this pathway could boost TLSs in tumors and enhance anti-tumor effects in the mice.
What Are Tertiary Lymphoid Structures?
Most immune cells congregate at specific anatomical sites called lymph nodes. This allows the immune cells to patrol tissues in the region and respond to perceived threats, including inflammation, injury, and cancer. It works well if the threat is short-lived. But some threats, such as cancer, cannot be immediately cleared.
When this occurs, the body creates aggregates of immune cells — the TLSs — at the diseased tissue site. These ad-hoc immune system outposts boost the immune response locally. TLSs pop up in many tissues, including most tumors, where they have been associated with a favorable response to immunotherapy drugs called checkpoint inhibitors. However, the signals that induce a TLS to form are not fully understood.
“The presence of TLSs in a tumor usually suggests a more active immune response, and is a positive sign in cancer,” Dr. Balachandran says. “But the molecules and cells involved in creating a TLS have remained unclear.”
The Cytokine IL-33 and ILC2 Immune Cells Are Critical to TLS Formation
Previous research published in Nature by Dr. Balachandran’s team found that an unusual type of immune cell called group 2 innate lymphoid cells (ILC2s) might have anti-cancer effects in pancreatic cancer. They discovered that a cell-signaling molecule (or cytokine) called interleukin-33 (IL-33) caused ILC2s and T cells to expand in tumors, which in turn had an anti-cancer effect in mice. Interleukins are a group of proteins that regulate the immune system and are involved in inflammatory and immune responses to infections and cancer.
The team’s new research reveals novel insights into IL-33’s anti-cancer function and how this molecule could be harnessed for immunotherapy.
Dr. Balachandran’s team found an association between markers of TLSs and IL-33 activity in human tumors, suggesting that the cytokine may play an important role in TLS formation. To test this, they compared mouse models of pancreatic cancer that either contained or lacked the gene that encodes IL-33. They found that TLSs could not form in the absence of IL-33.
To confirm the cytokine is required to induce TLSs, the researchers gave an artificially produced version of the mouse IL-33 protein directly to mice. This stimulated TLSs to form in pancreatic tumors. The team went on to show that IL-33 activates ILC2s to manage TLS formation and boost anti-tumor activity in mice, uncovering a new TLS-creating pathway.
Engineering an IL-33 Drug to Boost TLSs
The researchers then wondered if this pathway could be harnessed for immunotherapy. To develop an immunotherapy drug to activate the TLSs, the Balachandran Lab collaborated with the Tri-Institutional Therapeutics Discovery Institute to engineer an optimized human version of IL-33, a prototype drug candidate for future testing in cancer patients. As the human and mouse IL-33 proteins are very similar, the team was able to test the new molecule in mouse pancreatic cancer models. The team was encouraged to find that engineered human IL-33 expanded ILC2s and TLSs and boosted anti-cancer activity in the mice.
“When the human form of the compound has this effect in mice, it suggests the same pathway may exist in humans,” Dr. Balachandran says. The team is currently completing laboratory studies which will set the stage for clinical trials of the IL-33 drug candidate.
How TLSs May Enable Immunotherapy for Pancreatic Cancer
A new immunotherapy strategy would be especially important for treating pancreatic cancer. Checkpoint inhibitors have not been as successful treating this disease as they have been with other malignancies, such as rectal cancer and melanoma.
“Pancreatic cancer has been the poster child for cancers that don’t respond to currently available immunotherapy drugs,” Dr. Balachandran says. “Although early, our findings are an exciting proof-of-concept that targeting this novel pathway could be effective. We are excited to move an IL-33 drug candidate forward into phase 1 trials.”
