New Insights into Inflammatory Arthritis Linked to Cancer Drugs

 

Image credit: https://openai.com/index/dall-e/  

Cancer treatments called PD-1 inhibitors have been a real game-changer, helping the body's own immune system to fight off tumours. These drugs work by taking the 'brakes' off the immune system, allowing it to attack cancer cells more effectively. However, sometimes this revved-up immune response can go a bit too far and start attacking healthy parts of the body, leading to what are known as immune-related adverse events (irAEs).

One of the irAEs that doctors are seeing more and more is inflammatory arthritis (IA), where the joints become painful and swollen. While this can look a bit like another common condition called rheumatoid arthritis (RA), there are clues that the two might be different under the surface. For instance, PD-1-induced IA (or PD-1-IA for short) often doesn't show the same tell-tale signs in blood tests as RA, suggesting different things are going on. Plus, PD-1-IA can stick around for a good while even after the cancer treatment has stopped, which is a concern. Current ways of managing PD-1-IA mainly rely on expert opinion, and the long-term use of strong medications like steroids can worryingly interfere with the cancer-fighting effects of the PD-1 inhibitors. This means we really need to understand what's driving PD-1-IA so we can find better ways to treat it without compromising cancer therapy.

A recent study delved deep into the immune cells of patients with PD-1-IA, comparing them to those with RA and healthy individuals. The researchers looked at immune cells from the blood and also from the fluid in the affected joints using a detailed technique called single-cell RNA sequencing. This allowed them to see exactly what different types of cells were present and what genes they were switching on and off.

Key players: IL1Bhi macrophages and exhausted T cells:  The study uncovered some interesting differences between PD-1-IA and RA. One of the most striking findings was the predominant expansion of a specific type of immune cell called IL1Bhi myeloid cells in both the joint fluid and the blood of patients with PD-1-IA, but not in those with RA. These cells, particularly a type called IL1Bhi macrophagesfound in the joint fluid, seemed to be very inflammatory. The researchers even suggested that these inflammatory macrophages in the joint might actually originate from similar IL1Bhi monocytes found in the bloodstream.
Furthermore, they noticed a significant build-up of 'exhausted' CD8+ T cells (Texs) in the joint fluid of PD-1-IA patients. These T cells are a type of immune cell that can normally kill infected or cancerous cells, but in this case, they appear to be worn out. The study suggests that these IL1Bhi myeloid cells might be talking to these exhausted CD8+ T cells through specific communication pathways, potentially using molecules called CCR1-CCL5/CCL3 and CXCL10-CXCR3.

Unpacking the inflammatory response: When the researchers looked closer at the IL1Bhi macrophages, they found they had a lot of activity in pathways related to inflammation, such as those triggered by molecules like interferon-gamma, interferon-alpha, and TNF. They also had heightened activity in the NLRP3 inflammasome pathway, which is known to be a key trigger for producing IL-1β, the very molecule that gives the IL1Bhi cells their name. This suggests a powerful inflammatory process is underway in PD-1-IA, driven by these cells.
Intriguingly, when they looked at the pathway activity in patients whose PD-1-IA was in remission after treatment, the expression of IL1B was notably lower. This suggests that these IL1Bhi cells are linked to the active phase of the disease and could potentially be a way to monitor how well treatment is working.

The role of 'Worn-Out' T cells: The accumulation of exhausted CD8+ T cells in the joints of PD-1-IA patients was another key finding. These cells showed signs of exhaustion, expressing molecules like PDCD1 and CTLA4. Within this exhausted T cell population, the researchers identified subtypes, including some that looked like they might be self-renewing 'progenitor exhausted' cells, which could contribute to the long-term nature of the condition. They also found proliferative exhausted T cells that were churning out inflammatory molecules, further fueling the arthritis.

Cellular chit-chat: How immune cells communicate: To understand how these different immune cells might be interacting, the researchers used a database of ligand-receptor pairs – molecules that cells use to 'talk' to each other. They found much stronger interactions between myeloid cells and T cells in PD-1-IA compared to RA. The CCR1-CCL5/CCL3 and CXCL10-CXCR3 pathways seemed particularly important. They confirmed that the molecules involved in these pathways were indeed elevated in PD-1-IA patients, and experiments showed that these interactions could promote the movement of immune cells to the inflamed joints.

What does this mean for treatment? This research highlights that PD-1-IA has distinct immunological features compared to RA, with IL1Bhi macrophages and exhausted CD8+ T cells playing central roles. The identification of IL-1β and the CCR1 pathway as key players suggests they could be potential therapeutic targets for PD-1-IA. Blocking IL-1β, for instance, might help to dampen the excessive inflammation. Targeting TNF, another key inflammatory molecule identified in the study, might also be a more precise approach than broad immunosuppression and could potentially avoid interfering with the anti-tumour effects of PD-1 inhibitors.

Caveats: The researchers did note some limitations to their study, including the relatively small number of patients involved, which can affect the statistical power of the findings. Also, they had limited access to joint fluid samples for further validation. Future studies with larger groups of patients will be important to confirm these findings.

In conclusion: Despite these limitations, this study provides valuable new insights into the complex immune landscape of PD-1-IA. By identifying the key cell types and communication pathways involved, it opens up promising avenues for developing more targeted and effective treatments for this challenging side effect of cancer immunotherapy, ultimately aiming to alleviate patient suffering without compromising their fight against cancer.

Additional information: Single-cell profiling identifies IL1Bhi macrophages associated with inflammation in PD-1 inhibitor-induced inflammatory arthritis. Natue communications (2025). https://doi.org/10.1038/s41467-024-46195-x

Journal information: https://www.nature.com/ncomms/