Abstract
Despite great success in cancer immunotherapy, immune checkpoint-targeting drugs are not the most popular weapon in the armory of cancer therapy. Accumulating evidence suggests that the tumor immune microenvironment plays a critical role in anti-cancer immunity, which may result in immune checkpoint blockade therapy being ineffective, in addition to other novel immunotherapies in cancer patients. In the present review, we discuss the deficiencies of current cancer immunotherapies. More importantly, we highlight the critical role of tumor immune microenvironment regulators in tumor immune surveillance, immunological evasion, and the potential for their further translation into clinical practice. Based on their general targetability in clinical therapy, we believe that tumor immune microenvironment regulators are promising cancer immunotherapeutic targets. Targeting the tumor immune microenvironment, alone or in combination with immune checkpoint-targeting drugs, might benefit cancer patients in the future.
Highlights
To date, immune checkpoint (ICP)-targeting drugs, such as anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4), antiprogrammed cell death protein 1 (PD-1), and anti-PD-1 ligand 1 (PD-L1), have displayed considerable success in a number of cancer immunotherapies,[1,2,3,4] including melanoma, lung cancer, and other commonly diagnosed cancers
We aim to provide new insights into current cancer immunotherapy and reveal potential antitumor immunological targets in the tumor immune microenvironment (TIME) that overcome immunotherapeutic resistance in clinical applications
In a phase II study, the response rate was 38% in stage III/IV melanoma patients following administration of ipilimumab combined with dendritic cells (DCs)-vaccination therapy.[121]. These results suggest that the combination of ICP inhibitors (ICIs) with DC-vaccination therapy has a promising future
Summary
Tianyu Tang[1,2,3,4], Xing Huang 1,2,3,4, Gang Zhang[1,2,3,4], Zhengtao Hong[1,2,3,4], Xueli Bai[1,2,3,4] and Tingbo Liang[1,2,3,4]. Nuclear FAK promotes tumor growth and T-cell exhaustion by inducing CCL5 to recruit Treg cells.[78] FAK has been shown to negatively regulate T-cell receptor-mediated signaling by influencing the recruitment of C-terminal Src kinase members following TCR activation in T cells.[79] Preclinical data have shown that the FAK inhibitor VS-4718 reduced tumor fibrosis, decreased the number of myeloid-derived suppressor cells and prolonged survival in a mouse model.[80] when experiencing immune attack, cytotoxic T lymphocytes release interferon gamma (IFNγ) into the TIME, which further activates signal transducers and activators of transcription-related signaling pathways in cancer cells, in turn upregulating PD-L1 expression that suppresses the immune attack.[81,82,83,84] Acquired PD-1 blockade resistance in melanoma was found to correlate with JAK1 and JAK2 loss-of-function mutations Such mutations blocked IFNγ signaling, resulting in insensitivity to its antiproliferative effects on cancer cells.[85] These altered signaling pathways play a critical role in maintaining an immunosuppressive microenvironment, presenting a major obstacle for cancer immunotherapy. IL-2 was approved as the first immunotherapy for patients with advanced renal cell carcinoma and metastatic melanoma,[181] followed by the approval of IFN-α for renal cell leukemia, non-Hodgkin lymphoma and melanoma.[179,180] these cytokine strategies failed to live up to expectations raised by the results obtained in preclinical models, with clinical investigations revealing the narrow therapeutic windows and modest antitumor efficacy of such
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