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914 Regulating negative immune regulators to enhance immune checkpoint blockade antitumor potential
  1. Yared Hailemichael,
  2. Glenn Winn and
  3. Michael Davies
  1. The University of Texas MD Anderson Cancer Center, Houston, TX, United States


Background Understanding the exact immunobiology of immune checkpoint blockade (ICB)-related relapse would be essential to augmenting ICB-induced antitumor immunity and overcoming resistance. In response to ICB, a specific and effective immune response is induced. However, the levels of distinct immune cell subsets and the specific signals that draw them into a tumor microenvironment (TME) following broad application of cancer immunotherapies such as immune checkpoint blockade (ICB) remain poorly characterized. We previously showed that lymphocyte function associated antigen-1 (LFA-1) activation is critical for converting CD8 T cell exclusionary tumor microenvironment (TME) and allowing enhanced ICB-induced tumor control.1,2 Whereas very late antigen-4 (VLA-4) activation did not contribute to anti-CTLA-4 therapy antitumor response. Here, we evaluated the effect of integrin a4b7 blocker as a strategy to overcome immune resistance in the setting of combination immunotherapy (anti-CTLA-4, anti-PD-1 and/or anti-Lag-3).

Methods To evaluate synergy between ICB (anti-CTLA-4 and anti-PD-1 or anti-PD-1 and anti-Lag-3) and VLA-4 integrin blocker, once mice with B16 melanoma, Lewis lung carcinoma (LLC) or pancreatic adenocarcinoma (PAN-02) had developed tumors of approximately 20mm2, they were treated with either IgG control, VLA-4 blocker, ICB, or combination of both therapies together.

Results We observed no difference in therapeutic benefit between a4b7 blocker and IgG control (p<0.05) in all tumor models. Interestingly, we observed that a4b7 integrin blocker demonstrated therapeutic synergy with anti-CTLA-4 and anti-PD-1 but not anti-PD-1 and anti-Lag-3. Likewise, a4b7 integrin blocker in combination with anti-CTLA-4 and anti-PD-1 significantly enhanced antitumor response in PAN-02 (p<0.001) and LLC tumor (p<0.001) models. Initial immune infiltrates analysis shows improved antitumor response corresponded with increase in CD8+ Teff/Treg, CD4+ Teff/Treg ratios at the TME.

Conclusions Our preliminary results from treatment of mice implanted with tumor and receiving combination checkpoint blockade therapies suggest that a4b7 could potentially enhance intratumoral CD8+ effector T cell/Treg ratios to establish anti-tumor immunity.


  1. Hailemichael Y, et al. Cancer vaccine formulation dictates synergy with CTLA-4 and PD-L1 checkpoint blockade therapy. The Journal of Clinical Investigation 2018;128:1338–1354.

  2. Hickman A. et al. LFA-1 activation enriches tumor-specific T cells in a cold tumor model and synergizes with CTLA-4 blockade. The Journal of clinical investigation 2022.

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