LAUSR

Tumors generate an immune-suppressive environment that prevents effective killing of tumor cells by CD8 + cytotoxic T cells (CTL). It remains largely unclear upon which cell type and at which stage of the anti-tumor response mediators of suppression act. We have combined an in vivo tumor model with a matching in vitro reconstruction of the tumor microenvironment based on tumor spheroids to identify suppressors of anti-tumor immunity that directly act on interaction between CTL and tumor cells and to determine mechanisms of action. An adenosine 2A receptor antagonist, as enhanced by blockade of TIM3, slowed tumor growth in vivo. Engagement of the adenosine 2A receptor and TIM3 reduced tumor cell killing in spheroids, impaired CTL cytoskeletal polarization ex vivo and in vitro and inhibited CTL infiltration into tumors and spheroids. With this role in CTL killing, blocking A 2A R and TIM3 may complement therapies that enhance T cell priming, e.g. anti-PD-1 and anti-CTLA-4. Edmunds et al. examine how the adenosine receptor A 2A R and the checkpoint molecule TIM3 suppress the killing of Renca tumors expressing hemagglutinin (HA) as a model neo-antigen by CL4 TCR transgenic T cells, which recognize an HA peptide presented by H-2K d . The authors report that TIM3, which is upregulated on tumor-infiltrating CD8 + T cells after inhibition of A 2A R, and A 2A R impair the cytoskeletal polarization of the CL4 T cells.