MYC-Amplified Prostate Cancers Show Fewer Immune Cells, Hinting at Immunotherapy Resistance

Impact Journals LLC / Oncoscience

Prostate cancer that has spread beyond the prostate is difficult to treat, and immunotherapy, which has transformed outcomes for several other cancers, has shown limited success in most prostate patients. A study published in Oncoscience offers one possible explanation: the tumors that are most aggressive may also be the ones that have most effectively shut out the immune system.

MYC and metastatic disease

MYC is one of the most commonly amplified oncogenes across human cancers. When extra copies of the MYC gene accumulate in a tumor's DNA, the cancer typically becomes more aggressive, faster-growing, and harder to treat. In prostate cancer specifically, MYC amplification becomes more frequent as the disease progresses from localized tumors to metastatic castration-resistant prostate cancer (mCRPC), the stage at which treatment options narrow considerably.

Researchers at the University of South Florida and the H. Lee Moffitt Cancer Center, led by Sunny Kahlon with corresponding author George Blanck, asked a pointed question: does MYC amplification also correlate with reduced immune activity within the tumor? If so, that could explain why immunotherapy fails for many advanced prostate cancer patients, and potentially identify which patients are least likely to benefit.

Mining existing genomic data for immune signatures

The study used a computational approach rather than new clinical samples. The researchers analyzed publicly available genomics datasets, including TCGA-PRAD (The Cancer Genome Atlas prostate adenocarcinoma data) and multiple metastatic prostate cancer cohorts (WCDT-MCRPC and CMI-MPC). They quantified MYC copy numbers in each tumor, then measured the recovery of adaptive immune receptor (IR) recombination reads from the same tumors' RNA sequencing and whole-genome sequencing files.

Adaptive immune receptor recombination reads are molecular fingerprints of immune cell presence. When B cells and T cells develop, they rearrange their receptor genes through a process called V(D)J recombination, producing unique sequences. Finding these sequences in tumor sequencing data indicates that immune cells were present in the tumor at the time the sample was taken. Fewer reads suggest fewer infiltrating immune cells.

The pattern: more MYC, less immunity

The results were consistent across datasets. MYC-amplified metastatic tumors yielded significantly fewer recovered adaptive IR recombination reads compared to tumors without MYC amplification. The reduction was most pronounced for B cell-related reads (immunoglobulin heavy chain, kappa, and lambda), though T cell receptor reads were also reduced. MYC-amplified tumors also showed lower expression of immune-marker gene sets overall.

The clinical correlation matched the molecular pattern: MYC amplification was associated with worse progression-free survival, consistent with previous findings linking MYC to aggressive disease behavior.

A biomarker for immunotherapy selection?

The authors suggest that MYC amplification status could serve as a biomarker for predicting which metastatic prostate cancers are unlikely to respond to immune checkpoint blockade alone. If a tumor has amplified MYC and correspondingly reduced immune infiltration, standard immunotherapy may have less to work with. The authors propose that strategies to restore T cell or B cell infiltration, or to enhance their function within the tumor microenvironment, might be necessary to re-sensitize MYC-amplified tumors to immune-based treatments.

Significant limitations to consider

This study is entirely computational. The results derive from mining existing sequencing files, not from direct measurement of immune cell populations within tumors using techniques like immunohistochemistry or flow cytometry. Immune receptor recombination reads recovered from bulk sequencing are an indirect proxy for immune infiltration, and the sensitivity and specificity of this approach as a measure of tumor immunogenicity have not been fully validated.

The authors acknowledge that confirmatory measurements, such as PCR-based immune repertoire assays and prospective clinical sampling, will be needed to strengthen these conclusions. The study also does not establish causation: it shows a correlation between MYC amplification and reduced immune signatures, but does not prove that MYC amplification directly causes immune exclusion. Other genomic changes that co-occur with MYC amplification in metastatic disease could contribute to or account for the observed pattern.

The datasets used are retrospective and heterogeneous, drawn from different institutions with different sample processing protocols, which could introduce technical variation. The sample sizes for MYC-amplified tumors in some cohorts are modest, limiting statistical power for subgroup analyses.

Despite these caveats, the finding adds to a growing body of evidence that MYC amplification reshapes the tumor microenvironment in ways that extend beyond simple growth promotion. Whether this insight can be translated into improved patient selection for immunotherapy trials will depend on validation in prospective cohorts with paired genomic and immunological measurements.