Working to Improve Immunotherapy for Lung Cancer
Posted on by Dr. Francis Collins
For those who track cancer statistics, this year started off on a positive note with word that lung cancer deaths continue to decline in the United States . While there’s plenty of credit to go around for that encouraging news—and continued reduction in smoking is a big factor—some of this progress likely can be ascribed to a type of immunotherapy, called PD-1 inhibitors. This revolutionary approach has dramatically changed the treatment landscape for the most common type of lung cancer, non-small cell lung cancer (NSCLC).
PD-1 inhibitors, which have only been available for about five years, prime one component of a patient’s own immune system, called T cells, to seek and destroy malignant cells in the lungs. Unfortunately, however, only about 20 percent of people with NSCLC respond to PD-1 inhibitors. So, many researchers, including the team of A. McGarry Houghton, Fred Hutchinson Cancer Research Center, Seattle, are working hard to extend the benefits of immunotherapy to more cancer patients.
The team’s latest paper, published in JCI Insight , reveals that one culprit behind a poor response to immunotherapy may be the immune system’s own first responders: neutrophils. Billions of neutrophils circulate throughout the body to track down abnormalities, such as harmful bacteria and malignant cells. They also contact other parts of the immune system, including T cells, if help is needed to eliminate the health threat.
In their study, the Houghton team, led by Julia Kargl, combined several lab techniques to take a rigorous, unbiased look at the immune cell profiles of tumor samples from dozens of NSCLC patients who received PD-1 inhibitors as a frontline treatment. The micrographs above show tumor samples from two of these patients.
In the image on the left, large swaths of T cells (light blue) have infiltrated the cancer cells (white specks). Interestingly, other immune cells, including neutrophils (magenta), are sparse.
In contrast, in the image on the right, T cells (light blue) are sparse. Instead, the tumor teems with other types of immune cells, including macrophages (red), two types of monocytes (yellow, green), and, most significantly, lots of neutrophils (magenta). These cells arise from myeloid progenitor cells in the bone marrow, while T cells arise from the marrow’s lymphoid progenitor cell.
Though the immune profiles of some tumor samples were tough to classify, the researchers found that most fit neatly into two subgroups: tumors showing active levels of T cell infiltration (like the image on the left) or those with large numbers of myeloid immune cells, especially neutrophils (like the image on the right). This dichotomy then served as a reliable predictor of treatment outcome. In the tumor samples with majority T cells, the PD-1 inhibitor worked to varying degrees. But in the tumor samples with predominantly neutrophil infiltration, the treatment failed.
Houghton’s team has previously found that many cancers, including NSCLC, actively recruit neutrophils, turning them into zombie-like helpers that falsely signal other immune cells, like T cells, to stay away. Based on this information, Houghton and colleagues used a mouse model of lung cancer to explore a possible way to increase the success rate of PD-1 immunotherapy.
In their mouse experiments, the researchers found that when PD-1 was combined with an existing drug that inhibits neutrophils, lung tumors infiltrated with neutrophils were converted into tumors infiltrated by T cells. The tumors treated with the combination treatment also expressed genes associated with an active immunotherapy response.
This year, January brought encouraging news about decreasing deaths from lung cancer. But with ongoing basic research, like this study, to tease out the mechanisms underlying the success and failure of immunotherapy, future months may bring even better news.
 Cancer statistics, 2020. Siegel RL, Miller KD, Jemal A. CA Cancer J Clin. 2020 Jan;70(1):7-30.
 Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC. Kargl J, Zhu X, Zhang H, Yang GHY, Friesen TJ, Shipley M, Maeda DY, Zebala JA, McKay-Fleisch J, Meredith G, Mashadi-Hossein A, Baik C, Pierce RH, Redman MW, Thompson JC, Albelda SM, Bolouri H, Houghton AM. JCI Insight. 2019 Dec 19;4(24).
 Neutrophils dominate the immune cell composition in non-small cell lung cancer. Kargl J, Busch SE, Yang GH, Kim KH, Hanke ML, Metz HE, Hubbard JJ, Lee SM, Madtes DK, McIntosh MW, Houghton AM. Nat Commun. 2017 Feb 1;8:14381.
Non-Small Cell Lung Cancer Treatment (PDQ®)–Patient Version (National Cancer Institute/NIH)
Spotlight on McGarry Houghton (Fred Hutchinson Cancer Research Center, Seattle)
Houghton Lab (Fred Hutchinson Cancer Research Center)
NIH Support: National Cancer Institute
Thanks for sharing
It looks like PD-1 is a “T” cell activator. Where is the macrophages activator? We know that immune cells communicate. It looks like the PD-1 activator is a selective activator with limited application in this case.. Is there an activator that is stronger with a broader effect than PD-1 that would include the neutrophiles, macrophages and “T” cells? Maybe the wrong cell type is being activated here Maybe the correct immune cell type to activate first is the macrophages who in turn communicate with both neutrophiles and “T” cells. to initiate a broad comprehensive immune response to cancers. Has anyone tested GcMAF as this missing unknown broad immune activator? Until this is done, cancer research is beating around the bushes. There is something special about GcMAF that YOU need to investigate!!!! Stop hiding from GcMAF!!!!
The British have discovered a new unknown type of “T”cell that has built-in anti-cancer attributes with off-the-shelf capability. This will kill CAR-T therapy and cut the cost of this type of immunotherapy. Don’t let this discovery be suppressed in America like they did for GcMAF. You need to create a NIH project to find these cells and put them on-the-shelf. You also need to put human GcMAF on-the-shelf. If you combine these new “T” cells with GcMAF cancer can become just another curable disease when caught within a reasonable time!!!! We need a sensitive, cheap, easy to perform blood test for cancer like the Nagalase Blood Test. Can you help get FDA approval for this blood test? We can name it the Collins Blood Test if you like to leave your mark!
I will send the new “T” cell article (sent to you earlier) to all my Georgia representatives and continue to add new recipients to my emails. So I am not going to let anyone to continue to hide the discovery of GcMAF. It’ll take some time, but in the end the truth will come out!!!! You have been no help!!!! Add in the new wonder “T” cells with GcMAF and cancer can be cured in a matter of weeks instead of months. See GOD included the cure for cancer within His creation to await discovery by unbiased researchers. Unfortunately, American has pharmaceutically biased researchers and allows anything that does not comport with this bias to be suppressed..