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Introduction: The discovery of immune checkpoints and the development of their specific inhibitors was acclaimed as a major breakthrough in cancer therapy. However, only a limited patient cohort shows sufficient response to therapy. Hence, there is a need for identifying new checkpoints and predictive biomarkers with the objective of overcoming immune escape and resistance to treatment. Having been associated with both, treatment response and failure, LDL seems to be a double-edged sword in anti-PD1 immunotherapy. Being embedded into complex metabolic conditions, the impact of LDL on distinct immune cells has not been sufficiently addressed. Revealing the effects of LDL on T cell performance in tumor immunity may enable individual treatment adjustments in order to enhance the response to routinely administered immunotherapies in different patient populations. The object of this work was to investigate the effect of LDL on T cell activation and tumor immunity in-vitro.

Methods: Experiments were performed with different LDL dosages (LDLlow = 50 μg/ml and LDLhigh = 200 μg/ml) referring to medium control. T cell phenotype, cytokines and metabolism were analyzed. The functional relevance of our findings was studied in a HCT116 spheroid model in the context of anti-PD-1 blockade.

Results: The key points of our findings showed that LDLhigh skewed the CD4+ T cell subset into a central memory-like phenotype, enhanced the expression of the co-stimulatory marker CD154 (CD40L) and significantly reduced secretion of IL-10. The exhaustion markers PD-1 and LAG-3 were downregulated on both T cell subsets and phenotypical changes were associated with a balanced T cell metabolism, in particular with a significant decrease of reactive oxygen species (ROS). T cell transfer into a HCT116 spheroid model resulted in a significant reduction of the spheroid viability in presence of an anti-PD-1 antibody combined with LDLhigh.

Discussion: Further research needs to be conducted to fully understand the impact of LDL on T cells in tumor immunity and moreover, to also unravel LDL effects on other lymphocytes and myeloid cells for improving anti-PD-1 immunotherapy. The reason for improved response might be a resilient, less exhausted phenotype with balanced ROS levels.

... so low LDL is still good?

LDL alone has always been a bad marker for cardiovascular health. For one, 75% of heart attack victims have normal LDL range. Second, there are 4 types of LDL that are raised from different sources. Type 1 and type 2 LDL are harmless and actually beneficial but type 3 and type 4 are what is harmful. Type 1 and type 2 are raised via animal fats, type 3 and 4 are raised via processed foods, sugars, and simple starchy carbohydrates. It all relates the globule sizes as the larger type 1 and 2 are too large to get stuck on lesions in blood vessels but the smaller sized 3 and 4 are what is a risk for getting stuck in the artery walls. So just general LDL levels isn’t very informative, you need the more advanced testing that breaks it into subtypes.

In addition, the 5 meta studies performed over the last 20 years have never been able to draw a meaningful association between LDL and heart disease or early mortality. Meanwhile the these studies have always shown a direct strong correlation between blood triglyceride levels and early mortality. So when you get a blood panel, more important to look at the triglyceride levels than LDL. Hope this helps.

my most recent triglyceride level was 59 and LDL 62, so i'm hoping low is good.

The important thing is the ratio of your HDL to blood triglycerides. But the ultimate point is that LDL is not the bogeyman it’s made out to be. Most studies claiming things like meat are unhealthy is purely using LDL as the measuring stick to make that conclusion which the actual science shows is not the right parameter to make that distinction. Ultimately if you eat a diet filled with natural and fresh foods devoid of added sugars or processed foods then chances are your health is good.

Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model. That's what I'm screaming. Y'all with me? Who's coming with me?

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I thought this was the bad cholesterol?

ApoB is a better measurement as it contains all atherogenic particles.

So high LDL helped? Or made it worse?

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Helped, High LDL reduced IL-10 which enabled more CD4+T cells to differentiate into central memory-like phenotype - which is essential for prolonged anti-tumor immunity and durable response to checkpoint blockade.

There is a positive correlation between obesity and response to checkpoint blockade, this may be fishing out the reason why.

Interesting, I've also read those with elevated LP(a) tend to have less cancer occurrence, maybe it's linked, I'll try find more info

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2789456

In case you were interested