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<p>Cancer immunotherapy improves survival, yet many patients exhibit primary or acquired resistance. We established a combinatorial immunotherapy (COMBO) consisting of tumor antigen-specific Th1 cells and dual immune checkpoint blockade and aimed to noninvasively identify sites of immune activation associated with therapeutic response. Using <sup>NF-κB</sup>Luc-reporter mice, we longitudinally monitored NF-κB activation by using in vivo bioluminescence imaging in the tumor microenvironment (TME) and bone marrow (BM) of mice bearing OVA-expressing MC38 adenocarcinoma (responder) or B16 melanoma (non-responder). COMBO treatment induced tumor regression in OVA-MC38 but not OVA-B16 tumors. Responsive tumors showed significantly increased NF-κB activation in the TME, whereas resistant melanomas displayed no therapy-induced NF-κB activation. In contrast, BM NF-κB activity was reduced upon COMBO treatment in both models. Immunofluorescence and flow cytometry analyses revealed NF-κB activation in tumor-infiltrating MPO⁺ neutrophils and a concomitant reduction of CD11b⁺Gr-1<sup>high</sup> neutrophils in the BM in OVA-MC38 bearing mice, suggesting therapy-driven myeloid cell egress. Thus, therapeutic efficacy strongly correlated with NF-κB activation within the TME, while systemic BM changes reflected immune mobilization. Longitudinal imaging of NF-κB activity may enable early discrimination between therapy-sensitive and -resistant tumors in preclinical models.</p>

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Noninvasive in vivo imaging of NF-κB activation predicts immunotherapy response in solid tumors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Dimitri Stowbur,
  • Roman Mehling,
  • Philipp Knopf,
  • Barbara Francisca Schörg,
  • Dominik Sonanini,
  • Danielle Arnold-Schild,
  • Irene Gonzalez-Menendez,
  • Leticia Quintanilla-Martinez,
  • Birgit Fehrenbacher,
  • Martin Schaller,
  • Harald Carlsen,
  • Snehlata Kumari,
  • Bernd Jürgen Pichler,
  • Manfred Kneilling

摘要

Cancer immunotherapy improves survival, yet many patients exhibit primary or acquired resistance. We established a combinatorial immunotherapy (COMBO) consisting of tumor antigen-specific Th1 cells and dual immune checkpoint blockade and aimed to noninvasively identify sites of immune activation associated with therapeutic response. Using NF-κBLuc-reporter mice, we longitudinally monitored NF-κB activation by using in vivo bioluminescence imaging in the tumor microenvironment (TME) and bone marrow (BM) of mice bearing OVA-expressing MC38 adenocarcinoma (responder) or B16 melanoma (non-responder). COMBO treatment induced tumor regression in OVA-MC38 but not OVA-B16 tumors. Responsive tumors showed significantly increased NF-κB activation in the TME, whereas resistant melanomas displayed no therapy-induced NF-κB activation. In contrast, BM NF-κB activity was reduced upon COMBO treatment in both models. Immunofluorescence and flow cytometry analyses revealed NF-κB activation in tumor-infiltrating MPO⁺ neutrophils and a concomitant reduction of CD11b⁺Gr-1high neutrophils in the BM in OVA-MC38 bearing mice, suggesting therapy-driven myeloid cell egress. Thus, therapeutic efficacy strongly correlated with NF-κB activation within the TME, while systemic BM changes reflected immune mobilization. Longitudinal imaging of NF-κB activity may enable early discrimination between therapy-sensitive and -resistant tumors in preclinical models.