Sharma et al. demonstrated that the combination of the innate immune TLR1/2 agonist, Pam3CSK4, with anti-CTLA-4 in the B16F10 mouse melanoma model resulted in enhanced tumor rejection and improved survival with immunological memory. Enhanced efficacy depended on CD8+ and CD4+ T cells and correlated with increased IFNγ and granzyme B expression in intratumoral effector cells, and with increased intratumoral Treg depletion due to higher expression of FcγRIV on macrophages and increased ADCC of anti-CTLA-4-coated Tregs in the tumor. The combination was also effective in a pancreatic tumor model and may have translational value.
Contributed by Katherine Turner
Immune checkpoint inhibitors such as anti-CTLA-4 antibody are widely accepted therapeutic options for many cancers, but there is still a considerable gap in achieving their full potential. We explored the potential of activating the innate and adaptive immune pathways together to improve tumor reduction and survival outcomes. We treated a mouse model of melanoma with intratumoral injections of Toll-like receptor 1/2 (TLR1/2) ligand Pam3CSK4 plus i.p. injections of anti-CTLA-4 antibody. This combination treatment enhanced antitumor immune responses both qualitatively and quantitatively over anti-CTLA-4 alone, and its efficacy depended on CD4 T cells, CD8 T cells, Fcgamma receptor IV, and macrophages. Interestingly, our results suggest a unique mechanism by which TLR1/2 ligand increased Fcgamma receptor IV expression on macrophages, leading to antibody-dependent macrophage-mediated depletion of regulatory T cells in the tumor microenvironment and increasing efficacy of anti-CTLA-4 antibody in the combination treatment. This mechanism could be harnessed to modulate the clinical outcome of anti-CTLA-4 antibodies and possibly other antibody-based immunotherapies.
Author Info: (1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; nsharma1@mdanderson.org jallison@mdanderson.org. (2) Institut de Recherches Clin
Author Info: (1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; nsharma1@mdanderson.org jallison@mdanderson.org. (2) Institut de Recherches Cliniques de Montreal, Department of Medicine, University of Montreal, Montreal, QC H2W 1R7, Canada. (3) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; nsharma1@mdanderson.org jallison@mdanderson.org. Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
