Abstract

Checkpoint blockade can reverse T-cell exhaustion and promote antitumor responses. Although blocking the PD-1 pathway has been successful in Hodgkin lymphoma, response rates have been modest in B-cell non-Hodgkin lymphoma (NHL). Co-blockade of checkpoint receptors may therefore be necessary to optimize antitumor T-cell responses. Here, characterization of co-inhibitory receptor expression in intratumoral T cells from different NHL types identified TIGIT and PD-1 as frequently expressed co-inhibitory receptors. Tumors from NHL patients were enriched in CD8+ and CD4+ TEM cells that displayed high co-expression of TIGIT and PD-1, and co-expression of these checkpoint receptors identified T cells with reduced production of IFN-gamma, TNF-alpha and IL-2. The suppressed cytokine production could be improved upon in vitro culture in absence of ligands. Whereas PD-L1 was expressed by macrophages, the TIGIT ligands CD155 and CD112 were expressed by lymphoma cells in 39% and 50% of DLBCL cases and in some MCL cases, as well as by endothelium and FDCs in all NHLs investigated. Collectively, our results show that TIGIT and PD-1 mark dysfunctional T cells and suggest that TIGIT and PD-1 co-blockade should be further explored to elicit potent antitumor responses in patients with NHL.

View details for DOI 10.1158/2326-6066.CIR-18-0351

View details for PubMedID 30659053