3MO - LDH isoforms shape the immune microenvironment and impact treatment response and survival in metastatic melanoma

Background

Elevated lactate dehydrogenase (LDH) activity is linked to poor outcomes in various cancers, particularly in melanoma, where it stands as the most significant marker of negative prognosis, even with the most effective anticancer immunotherapies. While high LDH levels in the blood are often correlated with greater tumor burden, this is not always the case, and there is no conclusive evidence showing that LDH activity in the blood originates directly from tumor cells. Additionally, the role and distribution of the five LDH isoforms remain unclear.

Methods

We analyzed the enzymatic activities of total LDH and its isoforms in the plasma of 327 metastatic melanoma patients, including 224 with normal total LDH levels and 103 with elevated LDH levels, both prior to the start of immunotherapy and three weeks after the first injection. Additionally, we collected 62 metastasis biopsies for RNA sequencing and 68 biopsies to assess LDH isoform levels. PET-CT scans were also reviewed for 56 of these patients. Statistical analyses were conducted to investigate the source of circulating LDH and evaluate the influence of LDH isoforms on patient survival and their response to immune checkpoint inhibitors (ICI).

Results

We found that the repartition of isoforms was similar in the blood and in the metastases suggesting that high LDH activity originated from the tumors. Additionally, a low percentage of LDH1 and a high percentage of LDH4 were linked to reduced overall survival (LDH1: Cox 0.006; LDH4: Cox 0.019) and progression-free survival (LDH1: Cox 0.025; LDH4: Cox 0.050). Moreover, the LDH4/LDH1 ratio proved to be a stronger prognostic indicator than the individual isoforms (OS: Cox <0.001; PFS: Cox 0.004). Notably, this ratio allowed for better stratification of patients with poor prognosis, even among those with normal total LDH blood activity (OS: Cox <0.001; PFS: Cox 0.115). The LDH4/LDH1 ratio also predicted immune infiltration and response to immune checkpoint inhibitors (ICI), correlating with tumor aggressiveness (ρ 0.301; P 0.024), but not with tumor burden (ρ 0.013; P 0.925).

Conclusions

The LDH4/LDH1 ratio serves as a more reliable prognostic marker than the total LDH level generally used in clinical practice.

Legal entity responsible for the study

Institut Gustave Roussy.

Funding

Institut Gustave Roussy.

Disclosure

All authors have declared no conflicts of interest.