{
  "abstract": "Background Elevated B cell scores in human non-small cell lung cancer (NSCLC) correlate with response to neoadjuvant chemoimmunotherapy. 1 Additionally, neoadjuvant immune-based therapies can impact NSCLC-associated tertiary lymphoid structures (TLS),1 ectopic aggregates of B and T cells that form in proximity of tumors. While these findings implicate B cells in modulating immunotherapy efficacy in NSCLC, the underlying mechanisms remain unclear. Mouse models that account for B-cell neoantigens and recapitulate patients’ responses to immunotherapy are needed to elucidate the role of B-cell-driven anti-tumor T-cell immunity in NSCLC.Methods To develop a mouse model of NSCLC expressing both T- and B-cell neoantigens, we transduced 344SQ Kras G12D;p53R172HΔG mutant murine cells with the Hello construct (344SQ-Hello), encoding a fusion protein encompassing the B cell antigen HEL and the T cell antigens GP33–43 (CD8 T cell specific) and GP61–80 (CD4 T cell-specific). Mock lentivirus-transduced cells (344SQ-Lenti) were also produced. Hello or Lenti cells were injected in the flank of syngeneic mice to establish resectable tumors or in the lung via intratracheal delivery to obtain orthotopic tumors. Resectable tumors were measured three times per week to determine tumor growth; orthotopic tumors were monitored with weekly CT scans. The tumors’ immune contexture was characterized via immunohistochemistry and multiplex flow cytometry. To investigate response to immune-based therapy, resectable Hello tumors were treated with isotype control, chemotherapy (CT), PD-1 inhibition (i), PD-1i+CT, or PD-1i+CTLA-4i with or without CT.Results Resectable Hello tumors exhibited moderately reduced growth, increased CD8-to-CD4 T cell ratio, higher fractions of CD4 + effector/memory T cells and detectable GP33- and GP66-targeted T cells compared to Lenti, indicating anti-tumor immunity. While B cells infiltrated both Lenti and Hello tumors, T follicular helper cells, a subset known to interact with B cells, were distinctly increased in the Hello group. Lungs of mice bearing orthotopic Hello tumors displayed increased proportions of B cells expressing activation markers (CD69) and co-stimulatory molecules (CD86) compared to lungs of control mice, suggesting an engagement of B-cell responses. Additionally, lymphoid aggregates reminiscent of TLS formed in proximity of orthotopic Hello tumors. Finally, treatment of mice bearing resectable Hello tumors with chemoimmunotherapy yielded responses representative of those observed in patients, with dual immunotherapy with or without CT exhibiting the highest efficacy.Conclusions The 344SQ-Hello mouse model offers a novel in vivo platform to study the impact of neoadjuvant immune-based therapy on B-cell-driven immunity, the anti-tumor T-cell response and TLS formation and function in NSCLC.Reference Cascone T, William NW Jr, Weissferdt A, et al. Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial. Nat Med. 2023;29:593–604.",
  "authors": [
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Alessandra Vaccaro"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Xin Sun"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Armando J Ruiz-Justiz"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Michael Wang"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Cheuk Leung"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "John Le"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Lili Chen"
    },
    {
      "affiliations": [
        "Yale University School of Medicine, New Haven, CT, USA"
      ],
      "name": "Can Cui"
    },
    {
      "affiliations": [
        "Yale University School of Medicine, New Haven, CT, USA"
      ],
      "name": "Kelli Connolly"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Wei Hu"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Heather Y Lin"
    },
    {
      "affiliations": [
        "University of Pittsburgh, Pittsburgh, PA, USA",
        "UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA"
      ],
      "name": "Tullia C Bruno"
    },
    {
      "affiliations": [
        "Yale University School of Medicine, New Haven, CT, USA"
      ],
      "name": "Nikhil Joshi"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Tina Cascone"
    }
  ],
  "title": "709 A novel mouse model to investigate the impact of B cell-driven immunity in immunotherapy-treated non-small cell lung cancer",
  "uid": "33d43343-cb19-5191-92a1-632c9052c415"
}