Science Spotlight

MacPherson Lab puts immunologically cold cancers in the hot seat with combination therapy

From the MacPherson and Srivastava Labs, Cancer Basic Biology and Cancer Immunology Programs, Cancer Consortium.

Reading most Science Spotlight columns, you would correctly infer that immunotherapy is a big deal in medicine -- for cancer and beyond. Immunotherapies reinvigorate a patient’s immune system, retraining or re-sensitizing it so that it can lock onto targets it might have ignored before. For many patients with cancer, immunotherapy has made a drastic difference in quality and length of life. However, not all cancers are created equal: small cell lung cancer (SCLC), for instance, is considered “immunologically cold”, meaning the cancer cells manage to avoid immune recognition. Even if one were to reinvigorate the immune system, SCLC is often too stealthy to detect, possibly by hiding mutated proteins from patrolling immune cells. Enter Dr. Joseph Hiatt, a Research Associate in the MacPherson Lab (Human Biology and Public Health Sciences Divisions), and the study he recently led, published in Clinical Cancer Research.

“Immunotherapy has substantially improved outcomes for many patients with different types of lung cancer, but the gains for patients with SCLC have been modest at best,” explained Dr. Hiatt. “We wanted to develop a treatment strategy that could make immunotherapy more effective for patients with SCLC.” Other labs have recently shown that SCLC tumors with low neuroendocrine features and activation of the Notch signaling pathway may respond better to immune checkpoint blockade (ICB). Incredibly, the MacPherson Lab recently determined that inhibiting a protein called lysine-specific demethylase 1a (LSD1) led to both activation of Notch, and suppression of neuroendocrine transcriptional programs. Accordingly, the lab decided to see if LSD1 inhibition could improve ICB outcomes in a mouse model of SCLC, as well as in human and mouse cell culture experiments. “We made a model of SCLC in a mouse with an intact immune system so we could test the effectiveness of immunotherapy,” said Dr. Hiatt. “When we tried our treatment strategy (combining immunotherapy [anti-PD1] with an LSD1 enzyme inhibitor [bomedemstat]) in this system, we saw much better tumor control with both drugs than with either drug alone. This was a really exciting sign that our strategy might have merit. We then analyzed tumors and cells that had been treated with these drugs and found multiple signs of increased immune system activation, which was further validation of our approach.” The authors observed that cultured tumor cells treated with both drugs had higher expression of Major Histocompatibility Class-I (MHC-I), which is required for surveillance of cancer cells by immune cells, and increased killing by cytotoxic T cells. This combination therapy robustly stunted tumor growth, especially as compared to either bomedemstat or immunotherapy alone.

A graphic showing how the combination of bomedemstat and immunotherapy have a much stronger effect on tumor growth than either treatment alone.
In this study, Drs. Hiatt, MacPherson, and Srivastava describe how some treatments are more than the sum of their parts. Mouse models of small cell lung cancer are normally unresponsive to immunotherapies such as anti-PD1. However, treatment with a drug called bomedemstat in combination with anti-PD1 immunotherapy effected a significantly better outcome than either treatment on its own. Image provided by Dr. Joseph Hiatt.

“Immunotherapy has substantially improved outcomes for many patients with different types of lung cancer, but the gains for patients with SCLC have been modest at best,” explained Dr. Hiatt. “We wanted to develop a treatment strategy that could make immunotherapy more effective for patients with SCLC.” Other labs have recently shown that SCLC tumors with low neuroendocrine features and activation of the Notch signaling pathway may respond better to immune checkpoint blockade (ICB). Incredibly, the MacPherson Lab recently determined that inhibiting a protein called lysine-specific demethylase 1a (LSD1) led to both activation of Notch, and suppression of neuroendocrine transcriptional programs. Accordingly, the lab decided to see if LSD1 inhibition could improve ICB outcomes in a mouse model of SCLC, as well as in human and mouse cell culture experiments. “We made a model of SCLC in a mouse with an intact immune system so we could test the effectiveness of immunotherapy,” said Dr. Hiatt. “When we tried our treatment strategy (combining immunotherapy [anti-PD1] with an LSD1 enzyme inhibitor [bomedemstat]) in this system, we saw much better tumor control with both drugs than with either drug alone. This was a really exciting sign that our strategy might have merit. We then analyzed tumors and cells that had been treated with these drugs and found multiple signs of increased immune system activation, which was further validation of our approach.” The authors observed that cultured tumor cells treated with both drugs had higher expression of Major Histocompatibility Class-I (MHC-I), which is required for surveillance of cancer cells by immune cells, and increased killing by cytotoxic T cells. This combination therapy robustly stunted tumor growth, especially as compared to either bomedemstat or immunotherapy alone.

Dr. Shivani Srivastava, an Assistant Professor in the Human Biology Division and contributor to the study, added that “overall this was a great collaboration that enabled us to provide some insight into how LSD1 inhibition might be modulating the immune response to SCLC tumors, particularly by upregulating antigen presentation in tumor cells and making them more visible to the immune system.” However, this fast-paced work isn’t stopping there. “We have already designed and opened a clinical trial testing this strategy and we are currently enrolling patients at FHCC,” said Dr. Hiatt. “We are also doing more experiments in the lab to tease out details of how the combination is working, and we will do sophisticated testing on blood samples from patients in the trial to better understand why the treatment works better in some patients than others. [In the long term,] adding an LSD1 inhibitor to standard treatment might substantially increase the fraction of patients with SCLC who experience meaningful benefit from immunotherapy,” he concluded.

Hiatt JB, Sandborg H, Garrison SM, Arnold HU, Liao SY, Norton JP, Friesen TJ, Wu F, Sutherland KD, Rienhoff HY, Martins R, Houghton AM, Srivastava S and MacPherson D. 2022. Inhibition of LSD1 with Bomedemstat Sensitizes Small Cell Lung Cancer to Immune Checkpoint Blockade and T-Cell Killing. Clin Cancer Res. Oct 14;28(20):4551-4564. doi: 10.1158/1078-0432.CCR-22-1128. PMID: 35920742.

This work was supported by the National Institutes of Health, the National Cancer Institute, the National Heart, Lung, and Blood Institute, the National Health and Medical Research Council (Australia), Imago BioSciences, and Lyell Immunopharma.

Cancer Consortium members Dr. A McGarry Houghton (Cancer Immunology), Dr. Shivani Srivastava (Cancer Immunology), and Dr. David MacPherson (Cancer Basic Biology) contributed to this work.