Firing Up Cold Tumors.

Elucidating how tumor-intrinsic pathways regulate T cell infiltration in tumors is crucial for developing new therapeutic strategies for immune checkpoint blockade therapy. Here, we review recent progress on how these pathways orchestrate immune status in tumors and discuss the potential interventions for reprogramming the tumor microenvironment for cancer treatment.

Cheng WC ，Ho PC 《Trends in Cancer》

Killing the "BAD": Challenges for immunotherapy in pancreatic cancer.

Cancer regression often fails after systemic immune activation, especially for solid tumors due to their local immunosuppressive microenvironments. Among these, the pancreatic cancer microenvironment is unique and an important reason for resistance to anti-cancer treatments that include immunotherapy. In this review, the three main "BAD" characteristics that create and maintain this immunosuppressive microenvironment are discussed for effector T cells: Barriers to overcome, Attraction problems, and their Disabilities. These inhibit both effector T-cell activation and infiltration, reducing immunotherapy effectiveness. Combination approaches for killing the "BAD" aim to normalize the tumor microenvironment and are recommended to enhance anti-cancer immune-system efficacy in pancreatic cancer.

Li TJ ，Wang WQ ，Yu XJ ，Liu L ... -  《-》

Antitumor immunity is defective in T cell-specific microRNA-155-deficient mice and is rescued by immune checkpoint blockade.

MicroRNA-155 (miR-155) regulates antitumor immune responses. However, its specific functions within distinct immune cell types have not been delineated in conditional KO mouse models. In this study, we investigated the role of miR-155 specifically within T cells during the immune response to syngeneic tumors. We found that miR-155 expression within T cells is required to limit syngeneic tumor growth and promote IFNγ production by T cells within the tumor microenvironment. Consequently, we found that miR-155 expression by T cells is necessary for proper tumor-associated macrophage expression of IFNγ-inducible genes. We also found that immune checkpoint-blocking (ICB) antibodies against programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) restored antitumor immunity in miR-155 T cell-conditional KO mice. We noted that these ICB antibodies rescued the levels of IFNγ-expressing T cells, expression of multiple activation and effector genes expressed by tumor-infiltrating CD8+ and CD4+ T cells, and tumor-associated macrophage activation. Moreover, the ICB approach partially restored expression of several derepressed miR-155 targets in tumor-infiltrating, miR-155-deficient CD8+ T cells, suggesting that miR-155 and ICB regulate overlapping pathways to promote antitumor immunity. Taken together, our findings highlight the multifaceted role of miR-155 in T cells, in which it promotes antitumor immunity. These results suggest that the augmentation of miR-155 expression could be used to improve anticancer immunotherapies.

Huffaker TB ，Lee SH ，Tang WW ，Wallace JA ，Alexander M ，Runtsch MC ，Larsen DK ，Thompson J ，Ramstead AG ，Voth WP ，Hu R ，Round JL ，Williams MA ，O'Connell RM ... -  《-》

Checkpoint inhibitors in triple-negative breast cancer (TNBC): Where to go from here.

Advances in cancer immunotherapy and a growing body of research have focused on the role of the antitumor response in breast cancer. Triple-negative breast cancer (TNBC) is the most immunogenic breast cancer subtype, and there is strong evidence that tumor-infiltrating lymphocytes in TNBC have prognostic value and are associated with clinical outcome and improved survival. Evading antitumor immunity is a hallmark for the development and progression of cancer. Immunotherapy studies have focused on the role of the programmed cell death-1 (PD-1) receptor/programmed death-ligand 1 (PD-L1) pathway in maintaining immunosuppression in the tumor microenvironment. Blockade of the PD-1/PD-L1 axis has emerged as a promising therapeutic option to enhance antitumor immunity and is actively being investigated in TNBC, with encouraging results. In this article, the authors review the current literature on checkpoint inhibitors in TNBC with a focus on PD-1/PD-L1 antibodies and discuss combination strategies and novel approaches for improving antitumor immunity and clinical outcome. Cancer 2018;124:2086-103. © 2018 American Cancer Society.

Kwa MJ ，Adams S 《-》

Communication between EMT and PD-L1 signaling: New insights into tumor immune evasion.

Immune checkpoint blockage has been considered a breakthrough in cancer treatment, achieving encouraging anti-tumor effects in some advanced solid malignancies. However, low response rate and therapeutic resistance represent significant challenges in this field. In addition to its typical role in embryonic development and tissue fibrosis, epithelial-mesenchymal transition (EMT) plays a pivotal role in tumor immunosuppression and immune evasion. Previous studies revealed that EMT is associated with activation of different immune checkpoint molecules, including PD-L1. EMT-induced immune escape promotes cancer progression and may also provide a platform for discovery of novel therapeutic approaches and predictive biomarkers for checkpoint inhibitor therapeutic response. Here, we summarize recent findings focused on EMT-induced immune suppression and evasion in the tumor microenvironment (TME). EMT transcription factors (EMT-TFs), immune cells, cell plasticity and their regulatory role in the immune response are thoroughly reviewed. Bidirectional regulation between EMT and PD-L1 signaling is discussed in terms of cancer immune escape and possible combined therapies. Additionally, we investigated the value of preclinical or clinical trials using EMT targeted therapy combined with PD-L1 inhibitors. This review may help to further understand the role of EMT and PD-L1 signaling in cancer immune evasion. Meanwhile, additional molecular mechanistic studies and clinical trials are urgently needed.

Jiang Y ，Zhan H 《-》