Lee et al. investigated why cancer patients with liver mets have worse outcomes following anti-PD-1 therapy compared with those without liver mets. A dual-tumor (s.c. and liver) mouse model showed that a liver tumor antigen generated an immune response that led to systemic antigen-specific suppression in the s.c. tumor (not observed in a s.c. and lung model). Suppression was due to liver-specific Treg activation resulting in modulation of i.t. antigen-expressing CD11b+ monocytes and subsequent suppression of CD4+ and CD8+ effector T cells in the s.q. site. Suppression could not be reversed by anti-PD-1 unless Tregs were depleted or destabilized.
Contributed by Katherine Turner
ABSTRACT: Patients with cancer with liver metastasis demonstrate significantly worse outcomes than those without liver metastasis when treated with anti-PD-1 immunotherapy. The mechanism of liver metastases-induced reduction in systemic antitumor immunity is unclear. Using a dual-tumor immunocompetent mouse model, we found that the immune response to tumor antigen presence within the liver led to the systemic suppression of antitumor immunity. The immune suppression was antigen specific and associated with the coordinated activation of regulatory T cells (T(regs)) and modulation of intratumoral CD11b(+) monocytes. The dysfunctional immune state could not be reversed by anti-PD-1 monotherapy unless T(reg) cells were depleted (anti-CTLA-4) or destabilized (EZH2 inhibitor). Thus, this study provides a mechanistic understanding and rationale for adding T(reg) and CD11b(+) monocyte targeting agents in combination with anti-PD-1 to treat patients with cancer with liver metastasis.
Author Info: (1) Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. jeff.bluestone@ucsf.edu james.lee4@ucsf.edu. Sean N. Parker Autoimmu
Author Info: (1) Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. jeff.bluestone@ucsf.edu james.lee4@ucsf.edu. Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA 94143, USA. Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA. Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (2) Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA 94143, USA. Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA. (3) Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA 94143, USA. Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA. (4) Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA 94143, USA. Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA. QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia. (5) Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA 94143, USA. Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA. (6) Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA. Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94143, USA. (7) Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (8) Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA 94143, USA. jeff.bluestone@ucsf.edu james.lee4@ucsf.edu. Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA. Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA.
