Cancer immunotherapy is an innovative and exciting field of cancer treatment that harnesses the power of the immune system to fight cancer cells. Unlike traditional cancer treatments such as chemotherapy or radiation therapy, immunotherapy works by enhancing or reprogramming the body’s natural defenses to attack cancer cells. There are several types of immunotherapy currently being used to treat cancer, including immune checkpoint inhibitors, cancer vaccines, adoptive cell transfer, and cytokines. Immune checkpoint inhibitors are drugs that help the immune system recognize and attack cancer cells by blocking signals that tumors use to evade detection. These drugs target molecules such as PD-1 and CTLA-4, which are expressed on the surface of immune cells and inhibit their activity. By blocking these molecules, immune checkpoint inhibitors allow the immune system to mount a stronger attack against cancer cells. Cancer vaccines, on the other hand, work by stimulating the immune system to recognize and attack cancer cells. These vaccines contain proteins or other molecules that are specific to cancer cells, and when injected into the body, they trigger an immune response against those cells. Adoptive cell transfer involves extracting immune cells from a patient and genetically engineering them to target cancer cells more effectively. These modified cells are then infused back into the patient’s bloodstream, where they can recognize and attack cancer cells. Finally, cytokines are signaling molecules that help regulate the immune response. They can be used as cancer immunotherapies by stimulating the immune system to attack cancer cells more effectively.
While cancer immunotherapies, in some cases, these therapies have essentially cured advanced cancer patients who would have had no hope of survival otherwise. Yet for most cancers, immunotherapies are effective in only a minority of patients. In general, researchers still have much to learn about how anticancer immunotherapies work and how their effectiveness can be improved.
Neutrophils are a type of white blood cell that play an important role in the body’s immune response against infections and other foreign invaders. In cancer, neutrophils can either promote or inhibit tumor growth depending on the context. Recent research has suggested that neutrophils may also play a role in the effectiveness of immunotherapy. For example, some studies have found that patients with higher levels of neutrophils in their blood before starting immunotherapy have worse outcomes, suggesting that neutrophils may contribute to resistance to these treatments. Other research has suggested that neutrophils may be involved in the immune response to cancer cells targeted by immunotherapy. For example, some immunotherapies work by activating T cells, which can then attack cancer cells. Neutrophils may help amplify this response by releasing molecules that attract and activate T cells. However, neutrophils can also produce factors that can suppress the immune system, such as TGF-β, which can inhibit T cell function. This suggests that the relationship between neutrophils and immunotherapy is complex and likely depends on the specific type of immunotherapy, the type and location of cancer, and other factors. While the relationship between neutrophils and immunotherapy is still being studied, it is clear that neutrophils play an important role in the body’s immune response to cancer, and that understanding their interactions with immunotherapy may lead to new approaches for treating this disease. In a new study, published in the peer-reviewed Journal Cell, Weill Cornell Medicine scientists investigated how a T cell-based immunotherapy was able to destroy melanoma tumors even though many of the tumor cells lacked the markers or “antigens” targeted by the T cells. They found that the T cells, in attacking the tumors, activated a swarm of neutrophils which in turn killed the tumor cells that the T cells couldn’t eliminate. The findings could lead to new immunotherapies that harness this unexpected but potent antitumor immune response.
In the study, the researchers investigated an experimental immunotherapy that includes a drug to boost T cell activity and proliferation, plus T cells that have been engineered to recognize a melanoma-associated antigen. Tumors sometimes can evade an immunotherapy targeting a specific tumor antigen simply by ceasing to express that antigen the tumor cells that don’t express the antigen are called “escape variants.” However, the researchers found that their boosted T cell therapy could eliminate melanomas, in standard mouse models, even when a large portion of the melanoma cells lacked the targeted antigen, Trp1.
Ultimately, the authors determined that the initial anti-tumor activity of the T cells against Trp1-expressing melanoma cells triggered a secondary tumor-killing response from neutrophils. These white blood cells are best known as first-responders to infections and wounds. As members of the evolutionary older “innate” immune system, they do not target specific antigens in the way that T cells do. Yet the researchers concluded that the neutrophils summoned by their T-cell immunotherapy were indeed responsible for killing off the remaining, non-Trp1-expressing melanoma cells at least in part by secreting the highly reactive molecule nitric oxide.
The research team identified a characteristic gene expression pattern in the antitumor neutrophils, and found that in a widely used database on melanoma patients, the greater presence of this gene-expression in biopsied tumor samples was associated with better outcomes for patients. The results were especially surprising because prior studies have shown that neutrophils around a tumor often act as allies of the tumor the tumor co-opts them to help it survive and spread, which they do in part by suppressing other elements of antitumor immunity. The authors’ findings suggest that in the context of a strong immunotherapy that includes engineered T-cells targeting tumor antigens, and a general boosting of T-cell functions, neutrophils can play a significant antitumor role in fact, an essential role in mopping up escape variant tumor cells that would otherwise keep the tumor alive.
In conclusion, cancer immunotherapy is an exciting and rapidly evolving field that offers new hope for cancer patients. While not all patients respond to these treatments, for some, they can lead to long-term remission or even a cure. Ongoing research and clinical trials are exploring new approaches and combinations of therapies to further improve outcomes for patients with cancer.
Gungabeesoon J, Gort-Freitas NA, Kiss M, Bolli E, Messemaker M, Siwicki M, Hicham M, Bill R, Koch P, Cianciaruso C, Duval F, Pfirschke C, Mazzola M, Peters S, Homicsko K, Garris C, Weissleder R, Klein AM, Pittet MJ. A neutrophil response linked to tumor control in immunotherapy. Cell. 2023;186(7):1448-1464.e20.