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Epigenetic Differences May Explain Lack of Response to Metastatic Melanoma Immunotherapy

CHICAGO (GenomeWeb) – A study by researchers at the NYU Langone Medical Center and the Moffitt Cancer Center suggests tumor infiltrating cells (TIL) differ epigenetically in individuals with metastatic melanoma who do or do not respond to adoptive T cell therapy based around these TILs.

In conjunction with ongoing clinical trials aimed at treating metastatic melanoma, the team used the Illumina 450 array to assess DNA methylation patterns in TIL samples from two-dozen individuals being treated with TIL adoptive cell therapy, explained David Woods, a post-doctoral researcher at NYU Langone who presented the work during a session on developmental therapeutics in immunotherapy at the American Society of Clinical Oncology meeting this weekend.

The researchers also turned to chromatin immunoprecipitation in combination with sequencing to look at histone 3 acetylation in patient TIL samples, using magnetically labeled antibodies to separate CD4+ T cells from CD8+ T cells in the TIL population present at the cell infusion. At that time, expanded pools of TILs with reactivity against the tumor are returned to patients who have undergone so-called lymphodepletion of competing immune cells.

Around half of metastatic melanoma patients show some objective response to TIL adoptive cell therapies, Woods and his co-authors noted in the abstract for the presentation.

But while the five-year survival rate has climbed for individuals with metastatic melanoma since the advent of TIL adoptive cell therapy and other immune-based therapies, there is still a ways to go in applying these approaches more effectively and improving overall survival for many patients with advanced disease.

As it turned out, the team saw several differentially methylated sites in the genomes of TIL samples from individuals who responded to the treatment and those who didn't, particularly regions suspected of regulating CD4+ T cell lineage-related genes such as CD4, CD8, and RUNX3.

From those patterns, the researchers expected to see shifts in the expression of genes related to the CD4+ T cell lineage — patterns supported by their analysis of acetylated histone 3 marks in the TIL cells as well as NanoString-based profiling of related genes and microRNAs.

In particular, the epigenetic clusters detected in TIL samples from those who didn't respond to treatment suggest that CD8+ TILs more closely resembled CD4+ TILs in treatment non-responders, using both DNA methylation and histone acetylation patterns.

If that's the case, epigenetic differences and related gene expression features might also offer a means for distinguishing between individuals most apt to respond to TIL adoptive cell therapy.

Likewise, Woods explained, it may be possible to improve response to TIL adoptive cell therapy in metastatic melanoma patients by targeting epigenetic sites that differ between responders and non-responders and/or the genes they regulate when T cells are being grown in the lab.

In their preliminary experiments, for example, the researchers found that decreasing the level of 'double positive' T cells — those with both CD8+and CD4+ features — led to a rise in the lytic function of these TILs.

Those involved in the study argued that the results so far "highlight an unexplored mechanism of T cell dysfunction characterizing resistance to TIL [adoptive cell therapy]." The team hopes to verify and refine its understanding of the CD4+ and CD8+ T cell epigenetic differences in larger groups of patients with metastatic melanoma who are being treated with similar immunotherapy approaches.