Leukemia-associated macrophages, their role in the CLL Tumor Micro-environment and how they affect progression and therapy response

[AussieNeil]

Understanding how the CLL Tumor Micro-environment (TME) functions is crucial to improving CLL therapy. CLL cells are not as robust as healthy B cells and they rely on their created TME in the nodes and bone marrow for their survival. That's why it's so easy to kill CLL cells with in vitro testing - checking what happens to CLL cells exposed to potential drugs/supplements under a microscope, but then promising treatment candidates rarely work well in human clinical trials; the CLL TME counters the treatment. It's also why smudge cells (CLL cells with ruptured cell membranes) are often reported on our blood tests. Having a high count of smudge cells is actually a good prognostic marker.

Authors from the German CLL Study Group have just published this paper on the role of Macrophages and Nurse-like cells in the TME and how they influence targeted therapies; Impact of leukemia-associated macrophages on the progression and therapy response of chronic lymphocytic leukemia

sciencedirect.com/science/a...

As the paper notes, "The survival of a CLL cell strongly depends on its interaction with diverse factors in the tumor microenvironment (TME)".

Highlights:-

"..CLL remains a complex disease with many patients still experiencing relapse and unsatisfactory treatment responses. CLL cells are highly dependent on their pro-leukemic tumor microenvironment (TME), which comprises different cellular and soluble factors. A large body of evidence suggests that CLL-associated macrophages shaped by leukemic cells play a pivotal role in maintaining CLL cell survival. In this review, we summarize the pro-survival interactions between CLL cells and macrophages, as well as the impact of the current first-line treatment agents, including ibrutinib, venetoclax, and CD20 antibodies on leukemia-associated macrophages."

• Macrophages are important contributors to the progression of CLL.

• Frontline drugs not only target CLL cells but also affect macrophages substantially.

• Macrophages potentially influence the development of treatment resistance.

• Understanding CLL-macrophage interplay can lead to treatments overcoming resistance.

Headings:

1. Macrophages are indispensable supporters of chronic lymphocytic leukemia (CLL) cells

2. The generation and utilization of nurse-like cells (NLCs) have unveiled crucial mechanistic interactions between macrophages and CLL cells

3. Macrophages are strongly influenced by CLL therapy and contribute to therapy resistance

3.1. Ibrutinib and BTK inhibition

3.2. Venetoclax

3.3. Anti-CD20 monoclonal antibodies and the phagocytic role of leukemia-associated macrophages

4. Perspectives and Conclusion

Taken together, macrophages are major contributors not only to CLL progression but also to treatment responses and resistance development. Macrophages are the main actors in mAb treatment and play an important role in responses to several first-line treatment agents. While CLL treatment has advanced substantially over the past decade, resistance cases to these agents are constantly rising. This review underlines the importance of further investigations of macrophage polarization and functions under different treatment regimens. Comprehension of the complex effects of different immunomodulatory drugs on both leukemic cells and bystander compartments such as macrophages, as well as their impacts on the interplay between these cellular factors, may foster novel therapeutic combinations for tumor microenvironment remodeling and improved patient outcome.

Combined figures 2 and 3 from the paper, showing the interaction of ibrutinib, venetoclax with macrophages and rituximab and obinutuzumab with CLL cells respectively, are shown in the attached image.

We've had a few other posts recently regarding the TME;

• Targeting the tumor microenvironment for treating double refractory chronic lymphocytic leukemia posted by newyork917 healthunlocked.com/cllsuppo...

• Nurse like cells (NLC) and cll and monocyte levels posted by bachplayer13

• Latest study improves our understanding of the role the immune microenvironment plays in chronic lymphocytic leukemia posted by CLLerinOz

With thanks to CLLerinOz for bringing this paper to my attention

Neil

[spi3]

👣🙏Ty Neil - I do believe with information like this- gives many of us hope that we are on the right path to cure leukemia

[Sushibruno in reply to spi3]

🙏🏼🙏🏼

[Radarrick]

why is this so “Having a high count of smudge cells is actually a good prognostic marker.”

[AussieNeil Partner Administrator in reply to Radarrick]

This 2007 paper by Mayo Clinic CLL research authors, hypothesised that the percentage of smudge cells inversely correlates with the vimentin, a structural protein; Using smudge cells on routine blood smears to predict clinical outcome in chronic lymphocytic leukemia: a universally available prognostic test (2007) pubmed.ncbi.nlm.nih.gov/174...

Checking their patient database, they confirmed that "The percentage of smudge cells inversely correlated with vimentin expression (r=-0.57; P=.007). The median percentage of smudge cells was higher in patients with the mutated immunoglobulin heavy chain gene than in those with the unmutated immunoglobulin heavy chain gene (31% vs 13%; P=.02). Patients with less than 30% smudge cells had a median time from diagnosis to initial treatment of 72.7 months, whereas the median time from diagnosis to initial treatment in patients with 30% or more smudge cells was not reached (P=.001). "

Neil

[Zia2 in reply to AussieNeil]

My labs in Chicago while seeing my CLL specialist would read Smudge cells present but nothing else, no mention of percentage. Any thoughts why this may be?

[AussieNeil Partner Administrator in reply to Zia2]

That's standard, just mentioning "smudge cells present" on blood test reports. I also saw that on most of my reports prior to treatment. The Mayo paper from 2007 was just highlighting that their analysis from their CLL patient database, determined that additional percentage reporting of could provide a quick and easy prognostic indication to time to first treatment. I don't even know if Mayo Clinic subsequently implemented it for all their own CLL patients.

I mentioned the smudge cells, because;

1) It's an illustration of how vulnerable CLL cells are outside of their Tumor Micro-environment

2) Reports of them often appear on our test results and we shouldn't be concerned at seeing them mentioned, but rather the opposite.

Neil

[Zia2 in reply to AussieNeil]

Thank you. Hope you and yours are well.