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476 LAIR-1 inhibition enhances anti-PD-1 efficacy
  1. Yoshiko Takeuchi1,
  2. Corazon Arthur1,
  3. Heather Kohlmiller1,
  4. James White1,
  5. Betty Lee2,
  6. Bin Fan2,
  7. Jiawei Huang2,
  8. James Sissons2,
  9. Jonathan Sitrin2,
  10. Lee Rivera2 and
  11. Robert Schreiber1
  1. 1Washington University School of Medicine, Saint Louis, MO, United States
  2. 2NGM Biopharmaceuticals Inc., South San Francisco, CA, United States


Background Leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is an immune inhibitory collagen-binding receptor that is aberrantly expressed in tumors. Recent work by others has led to conflicting views of immunoinhibitory versus immunoenhancing roles for LAIR-1 in solid tumors. Here, using well-defined syngeneic mouse tumor models, we assess the antitumor efficacy of LAIR-1 inhibition/depletion either alone or in combination with anti-PD-1.

Methods To evaluate the effect of LAIR-1 inhibition on in vivo tumor growth and control, we used either Lair1 –/– mice or a LAIR-1 blocking monoclonal antibody (mAb). We used two antigenically distinct MCA-induced C57Bl/6 strain sarcoma lines (1956 and 7347), a 129S6 strain sarcoma line (F244) and a PD-1 sensitive clone of C57Bl/6 MC38 (MC38-5s). To assess the effects of LAIR-1 deficiency on tumor immunity, we injected either 1956, 7347, or MC38-5s cells into either syngeneic Lair1 –/– or WT mice, and 10 days later, when tumor-bearing WT mice became insensitive to anti-PD-1 therapy, initiated either anti-PD-1 or Ctrl mAb therapy. To evaluate the efficacy of LAIR-1 blocking mAb as monotherapy or in combination with anti-PD-1, we treated 1956 or 7347 bearing WT C57Bl/6 mice and F244 bearing WT 129S6 mice continuously with either anti-LAIR-1 or Ctrl mAb. Ten-days after tumor inoculation, mice were additionally treated with either anti-PD-1 or Ctrl mAb.

Results Whereas 89% of anti-PD-1 treated Lair1 –/– mice rejected 1956 sarcomas, only 22% of Ctrl mAb treated Lair1 –/– mice and 6% of anti-PD-1 treated WT mice rejected their tumors. PD-1 blockade of Lair1 –/– mice bearing 7347 sarcomas or MC38-5s tumors induced similar rejection responses. In WT mice, the anti-LAIR-1 and anti-PD-1 combination induced better anti-tumor efficacy than anti-LAIR-1 or anti-PD-1 monotherapy. Flow cytometry analysis revealed that tumor-specific T cells were significantly increased in anti-PD-1 treated Lair1 –/– mice compared to anti-PD-1 treated WT mice. Depletion of CD4+ and/or CD8+ T cells in Lair1 –/– mice inhibited anti-PD-1 mediated tumor rejection. High dimensional profiling via CyTOF analyses of the myeloid cell compartment from 1956 tumors in Lair1 –/– mice treated with either anti-PD-1 or Ctrl mAb revealed a selective increase over similarly treated WT mice in a macrophage cluster expressing CD206 and folate receptor-b, suggesting that development of this macrophage cluster was LAIR-1 dependent.

Conclusions This study shows that inhibition of LAIR-1 in tumor bearing mice sensitizes advanced tumors to anti-PD-1 treatment.

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