{
  "abstract": "Background The B regulatory cell (Breg) in the tumor microenvironment (TME) has emerged as a pivotal immune checkpoint. 1–3 Despite their recognized significance, critical gaps in understanding Bregs remain. Methods and Results Our studies have identified Src homology region 2 domain-containing phosphatase-2 (SHP2, encoded by Ptpn11) in B cells as a central in situ signaling hub, integrating multiple inflammatory signals derived from tumoral KrasG12D to drive Breg induction and proliferation. Pharmaceutical SHP2 inhibitor (SHP2i) or its genetic ablation specifically in B cells (Cd79α-Cre; Ptpn11flfl ) disrupted the mutant KRAS-mediated Breg-inducing signals, curbed aberrant Breg expansion, corrected their altered distribution in the TME, and, crucially, suppressed their immunosuppressive properties (figure 1). Conversely, B cells with a knock-in drug-resistant mutation (Ptpn11P491Q , Cd79α-Cre; Ptpn11inPQPQ ) retained all Breg phenotypes upon the treatment of a SHP2i (figure 1). Further studies using mice featuring an enzymatically inactive SHP2 (Cd79α-Cre; Ptpn11C459E/fl ) revealed that both the phosphatase activity and the adaptor function of SHP2 are essential for acting as a binary live/dead switch for Breg generation (figure 2). Importantly, B cell depletion in Cd79α-Cre; Ptpn11flfl mice accelerates tumor growth, indicating that SHP2-deficient B cells possess anti-tumor potential.Conclusions Our findings highlight the function of SHP2 as a molecular switch between pro- and anti-tumor immunity of B cells in the context of Kras-driven TME.References Laumont CM, Nelson BH. B cells in the tumor microenvironment: Multi-faceted organizers, regulators, and effectors of anti-tumor immunity. Cancer Cell 2023;41(3):466-489.Schioppa T, et al. B regulatory cells and the tumor-promoting actions of TNF-α during squamous carcinogenesis. Proc Natl Acad Sci U S A 2011;108(26):10662-7.Shang J, Zha H, Sun Y. Phenotypes, functions, and clinical relevance of regulatory B cells in cancer. Front Immunol 2020;11:582657.Abstract 749 Figure 1a-b. SHP2i resistance or SHP2 loss in B cells has significant effects on KP tumor growth. KP tumor growth following the treatment of Veh or SHP099 in WT control (Mb1cre/wt) vs. Mb1cre-/Ptpn11inPQPQ or Ptpn11 flfl mice.miceAbstract 749 Figure 2Flow-cytometric analyses of cytokine profiles in B cells in TME upon SHP2i (SHP099, 10µM) treatments or/and genetic modification as indicated",
  "authors": [
    {
      "affiliations": [
        "Laura and Issac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA"
      ],
      "name": "Benjamin Neel"
    },
    {
      "affiliations": [
        "Laura and Issac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA"
      ],
      "name": "Kwok-Kin Wong"
    },
    {
      "affiliations": [
        "Laura and Issac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA"
      ],
      "name": "Yi Ban"
    }
  ],
  "title": "749 SHP2: A binary switch for rogue B cells in the microenvironment of Kras-mutant lung cancer",
  "uid": "d8f806e9-7cf2-53ff-a653-97a864d2d83c"
}