Macrophages predict response to immunotherapy in Merkel cell carcinoma

From the Nghiem lab, Fred Hutch Clinical Research Division & UW Dermatology

Why do some people respond to immunotherapy and others progress? Can we predict who will and who won’t respond? Can we develop new therapies or combine therapies to help those patients who don’t respond? These are the questions being addressed in a new paper in Clinical Cancer Research by Dr. Paul Nghiem, Director of the Skin Oncology Clinical Program at Fred Hutch and Chair of Dermatology at UW Medicine, and his team.

So, what is immunotherapy? In brief, it is a type of cancer treatment that reactivates a patient’s immune system to fight their cancer. It can provide long lasting benefit even for patients whose tumors have spread to other parts of the body or progressed while on other treatments. Immunotherapy is not a silver bullet, however, as only 20-40% patients with the most common cancer types, (such as lung, breast, and prostate) respond and it is challenging to predict who will and will not respond to this type of treatment.

One cancer where immunotherapy is turning the tide is Merkel cell carcinoma (MCC), a rare but deadly skin cancer, where response rates are above average at ~50%. About 4 in 5 MCC tumors are caused by the Merkel cell virus and the virus-negative MCC tumors are caused by UV damage from excessive sun exposure. Despite their different origins, both types of MCC are highly “immunogenic” – meaning a patient’s immune system should be able to detect the tumor cells as foreign and eliminate them. In patients with MCC, their immune system is no longer able to fight off and kill cancer cells, leading to their tumor steadily growing and spreading over time if left untreated. That’s where immunotherapy comes in to help reactivate the immune system and clear tumors.

T cells (purple) and macrophages (green, yellow, red) correlate with response to immunotherapy.
T cells (purple) and macrophages (green, yellow, red) correlate with response to immunotherapy. Image modified from original article.

But what happens in the other 50% of patients who don’t respond to immunotherapy? Dr. Nghiem’s previous work showed that MCC patients whose tumors contain higher numbers of CD8+ T cells, a type of immune cell that can kill cancer cells, have better outcomes including longer overall survival. However, some patients with high numbers of T cells in their tumors still progress while on immunotherapy. So why are these MCC tumors with lots of killer T cells not responding to immunotherapy?

In their latest paper, Dr. Shira Tabachnick-Cherny, lead author and postdoctoral fellow in the Nghiem lab, decided to look at what other immune cells are found in MCC tumors and their correlation with immunotherapy response. “While T cells have long been recognized as key players in this cancer type, the role of myeloid cells has remained relatively uncharted territory” Shira says. Myeloid cells are immune cells that can either enhance or suppress T cell responses depending on the context. Analyzing patient samples prior to immunotherapy, Dr. Tabachnick-Cherny found that macrophages were the dominant type of myeloid cell found in MCC tumors. Macrophages play an important role in alerting other immune cells to invading pathogens but in tumors they often suppress immune responses. Dr. Tabachnick-Cherny’s analysis revealed that macrophages from MCC tumors have high levels of genes associated with immune suppression.

Next, they teamed up with Fred Hutch Experimental Histopathology Core, part of the Cancer Consortium Shared Resources, to analyze the macrophages and T cells in samples from MCC patients treated with immunotherapy with varying responses. They found that patients with the best responses to immunotherapy tended to have lots of T cells but few macrophages in their tumors. Conversely, patients who had lots of T cells in their tumors but still progressed on immunotherapy usually had lots of macrophages, suggesting that macrophages block T cells from responding to immunotherapy. Interestingly, they found no difference in the number of macrophages near T cells in patients who either responded or progressed on immunotherapy, suggesting that macrophages inhibit T cell function by secreting immunosuppressive molecules into tumors rather than through direct interactions.

So far, these exciting new results demonstrate a correlation between the ratio of macrophages to T cells in patients with high T cells but do not respond to immunotherapy. In the future, Dr. Nghiem’s team aims to investigate whether targeting macrophages can help patients who don’t respond to immunotherapy: “There are several therapeutic approaches […] that may make sense to consider based on these findings. For example, LILRB receptors are a plausible way to target such [macrophages] and anti-LILRB drugs are now in clinical trials, with some MCC patients showing benefit” Dr Nghiem says.  Furthermore, such approaches may show benefit in other cancers in which macrophages play a significant role in immune evasion and resistance to immunotherapy.

This work was funded by the National Institutes of Health, National Cancer Institute and Odyssey Group Foundation.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium member Dr. Paul Nghiem contributed to this work.

Tabachnick-Cherny S, Pulliam T, Rodriguez HJ, Fan X, Hippe DS, Jones DC, Moshiri AS, Smythe KS, Kulikauskas RM, Zaba L, Paulson KG, Nghiem P. Characterization of immunosuppressive myeloid cells in Merkel cell carcinoma: correlation with resistance to PD-1 pathway blockade. Clinical Cancer Res. 2023