Identification of biomarkers related to immunotherapeutic response and resistance could support the rational design of complementary therapies in which the additional targeting of those biomarkers would lead to more effective cancer therapies. In depth mechanistic studies of PD-1/PD-L1 blockade in vivo may lead to rational design of improved co-treatment protocols. Indeed, recent studies reported co-treatment regimens to PD-1 blockade. However, tumor-specific T cells are also restrained by several other inhibitory mechanisms, which put forward the premise that PD-1/PD-L1-based monotherapies could be enhanced so that the majority of patients will have durable clinical benefit. Studies have shown that T cells are however partially inhibited by PD-1/PD-L1 interactions and releasing this constraint by blocking the PD-1 pathway can to some extent reinvigorate T cells leading to clinical benefit in a number of cancer patients. Therefore, there is a need for more effective treatment regimens, like combinatorial immunotherapies, which offer an attractive avenue to improve the efficacy and the duration of the tumor specific T-cell response.īoth CD8 + and CD4 + T cells can mount responses against many human cancer types, especially those with higher mutational burden. Despite these encouraging results, still only a fraction of patients show durable responses, whereas the majority of treated patients show no beneficial clinical response. ![]() Especially, clinical trials with antibodies that block the interaction between the inhibitory receptor PD-1, expressed on previously activated T cells, with its broadly expressed ligand PD-L1, resulted in unprecedented clinical response rates for patients with advanced cancer. Immunotherapy has become an important treatment option for cancer patients. These T AI cells can be targeted by combined immunotherapy leading to improved survival. This study shows the presence of T cell subsets in the tumor micro-environment expressing both activating and inhibitory receptors. Moreover, T AI cells were also found in the tumor-microenvironment of colorectal cancer patients. By therapeutically co-targeting these molecules on the T AI cell subsets in vivo by agonistic and antagonist antibodies, we were able to enhance PD-L1 blockade therapy as evidenced by an increased number of T AI cells within the tumor micro-environment and improved tumor protection. PD-L1 blockade induced selectively the expansion of tumor-infiltrating CD4 + and CD8 + T-cell subsets, co-expressing both activating (ICOS) and inhibitory (LAG-3, PD-1) molecules. Immune profiling was extended to the tumor microenvironment of colorectal cancer patients. Findings were further examined and validated by flow cytometry and by functional in vivo experiments. To establish high-dimensional immune signatures of immunotherapy-specific responses, the tumor microenvironment was analyzed by CyTOF mass cytometry using 38 cellular markers. ![]() Mice bearing subcutaneous MC-38 tumors were treated with blocking PD-L1 antibodies. Here, we aimed at deciphering the mechanisms governing the response to PD-1/PD-L1 checkpoint blockade to support the rational design of combination immunotherapy. ![]() Combination immunotherapy offers an attractive avenue to develop more effective cancer therapies by improving the efficacy and duration of the tumor-specific T-cell response. The clinical benefit of immunotherapeutic approaches against cancer has been well established although complete responses are only observed in a minority of patients.
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