% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Handke:305081,
      author       = {A. Handke$^*$ and L. Lopes and C. Kesch$^*$ and C. Darr$^*$
                      and E. Davicioni and K. Shi and T. Telli$^*$ and W. P.
                      Fendler$^*$ and K. Herrmann$^*$ and K. Lückerath$^*$ and B.
                      Hadaschik$^*$ and R. Seifert$^*$},
      title        = {{T}ranscriptomic {P}rofiling of the {T}umor {I}mmune
                      {M}icroenvironment {R}eveals {P}rognostic {M}arkers in
                      m{CRPC} {P}atients {T}reated with {L}u{PSMA} {T}herapy.},
      journal      = {Theranostics},
      volume       = {15},
      number       = {18},
      issn         = {1838-7640},
      address      = {Wyoming, NSW},
      publisher    = {Ivyspring},
      reportid     = {DKFZ-2025-02033},
      pages        = {9447 - 9458},
      year         = {2025},
      abstract     = {Rationale: The mode of action of [177Lu]Lu-PSMA-617
                      (LuPSMA) therapy is not fully understood and a relevant
                      fraction of patients show treatment failure. Therefore, this
                      study aimed to investigate the prognostic significance of
                      immune suppression in the tumor immune microenvironment
                      (TME) of LuPSMA therapy patients. Methods: Tumor tissue
                      samples from 61 patients, who were referred for LuPSMA from
                      March 2018 until March 2022, were retrieved. Among these, 40
                      patients fulfilled all criteria and were therefore included
                      in the analysis. Of these, 3 patients had two biopsies;
                      prior and under systemic treatment, which is why we analyzed
                      43 samples: 29 $(67\%)$ with treatment-naïve tissues
                      samples (cohort 1) and 14 $(33\%)$ during systemic
                      treatment. Patients were followed up to assess overall
                      survival. We examined gene expression and immune cell counts
                      (derived from gene expression data) in the two sub-cohorts
                      through transcriptome profiling with the Decipher prostate
                      assay (Veracyte, San Diego, CA), a subset of these patients
                      has been described previously. Results: In the total cohort,
                      the ratio of activated (M1)/naive (M0) macrophages (HR =
                      0.90 [0.84-0.98]; p = 0.009) was a significant
                      prognosticator of OS. In cohort 1, PD-L2 expression (HR =
                      1.07 [1.02 - 1.11]; p = 0.003)) and the M1/M0 ratio
                      signature (HR = 0.89 [0.81-0.99]; p = 0.026) were
                      significant independent prognostic factors of OS when
                      analyzed together in a multivariate analysis. AR gene
                      expression was significantly elevated in cohort 2 compared
                      to 1 (p < 0.001). Several DNA repair signatures analyzed
                      were significantly higher in cohort 2 than in cohort 1 (p <
                      0.05). In cohort 2, PD-L2 expression (HR = 0.87 [0.77 -
                      0.98]; p = 0.017) emerged as an independent prognostic
                      factor associated with improved OS when included in a
                      multivariate model with the immune 190 score, a negative
                      prognosticator in this analysis (HR = 1.25 [1.02 - 1.53]; p
                      = 0.028). Conclusions: The ratio of M1/M0 macrophages was
                      associated with favorable outcome of LuPSMA in the total
                      cohort of patients. In treatment-naive patient samples,
                      PD-L2 expression was associated with unfavorable, whereas
                      M1/M0 macrophages with favorable outcomes, which might
                      indicate that immune checkpoint inhibition could be a
                      combination partner of LuPSMA therapy. In patient biopsy
                      samples acquired after the start of systemic treatment, AR
                      gene expression and DNA repair signatures appear to be
                      significantly altered and PD-L2 became a protective marker.},
      keywords     = {Humans / Tumor Microenvironment: immunology / Tumor
                      Microenvironment: genetics / Male / Prognosis / Middle Aged
                      / Gene Expression Profiling: methods / Aged / Transcriptome
                      / Biomarkers, Tumor: genetics / Decipher prostate assay
                      (Other) / PD-L2. (Other) / [177Lu]Lu-PSMA-617 therapy
                      (Other) / prostate cancer (Other) / transcriptomic profiling
                      (Other) / Biomarkers, Tumor (NLM Chemicals)},
      cin          = {ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41041047},
      pmc          = {pmc:PMC12486015},
      doi          = {10.7150/thno.113614},
      url          = {https://inrepo02.dkfz.de/record/305081},
}