Although the clinical development of immune checkpoint inhibitors (ICIs) therapy has ushered in a new era of anti-tumor therapy, with sustained responses and significant survival advantages observed in multiple tumors, most patients do not benefit. Therefore, more and more attention has been paid to the identification and development of predictive biomarkers for the response of ICIs, and more in-depth and comprehensive understanding has been continuously explored in recent years. Predictive markers of ICIs efficacy have been gradually explored from the expression of intermolecular interactions within tumor cells to the expression of various molecules and cells in tumor microenvironment, and been extended to the exploration of circulating and host systemic markers. With the development of high-throughput sequencing and microarray technology, a variety of biomarker strategies have been deeply explored and gradually achieved the process from the identification of single marker to the development of multifactorial synergistic predictive markers. Comprehensive predictive-models developed by integrating different types of data based on different components of tumor-host interactions is the direction of future research and will have a profound impact in the field of precision immuno-oncology. In this review, we deeply analyze the exploration course and research progress of predictive biomarkers as an adjunctive tool to tumor immunotherapy in effectively identifying the efficacy of ICIs, and discuss their future directions in achieving precision immuno-oncology.

Friend leukemia virus integration 1 (FLI1), an ETS transcription factor family member, acts as an oncogenic driver in hematological malignancies and promotes tumor growth in solid tumors. However, little is known about the mechanisms underlying the activation of this proto-oncogene in tumors. Immunohistochemical staining showed that FLI1 is aberrantly overexpressed in advanced stage and metastatic breast cancers. Using a CRISPR Cas9-guided immunoprecipitation assay, we identify a circular RNA in the FLI1 promoter chromatin complex, consisting of FLI1 exons 4-2-3, referred to as FECR1.Overexpression of FECR1 enhances invasiveness of MDA-MB231 breast cancer cells. Notably, FECR1 utilizes a positive feedback mechanism to activate FLI1 by inducing DNA hypomethylation in CpG islands of the promoter. FECR1 binds to the FLI1 promoter in cis and recruits TET1, a demethylase that is actively involved in DNA demethylation. FECR1 also binds to and downregulates in trans DNMT1, a methyltransferase that is essential for the maintenance of DNA methylation. These data suggest that FECR1 circular RNA acts as an upstream regulator to control breast cancer tumor growth by coordinating the regulation of DNA methylating and demethylating enzymes. Thus, FLI1 drives tumor metastasis not only through the canonical oncoprotein pathway, but also by using epigenetic mechanisms mediated by its exonic circular RNA.

Over the last decade, based on the extensive development of preclinical animal studies and clinical trials, the efficacy, and mechanisms of immunotherapy have been fully explored. Significant and lasting clinical responses with immunotherapy provide a new breakthrough treatment for a variety of refractory cancer histologies, which gradually change the treatment pattern of tumors. However, although immune checkpoint inhibitor drugs are promising for achieving longer-term efficacy, their benefits in the overall population are still very low, such as low frequency of response in some common tumor types such as breast and prostate, and heterogeneity in the degree of response among different tumor lesions in the same patient, making immunotherapy with many limitations and challenges. Most patients do not respond to immunotherapy or inevitably develop resistance to treatment after a period of treatment, manifesting with primary resistance or acquired resistance who initially respond to treatment. The mechanisms of tumor immune resistance are very complex and involve multiple aspects such as genes, metabolism, inflammation, and abnormal neovascularization. Currently, many mechanisms of immunotherapy resistance have been characterized, and more continue to be uncovered. These efforts can improve the quality of medical care for cancer diagnosis and treatment, which improve the quality of life of patients, and finally lead to accurate individualized treatment. This review discusses mechanisms of cancer immunotherapy resistance including tumor-intrinsic factors and tumor-extrinsic factors.

γδ T cells are a distinct subgroup of T cells containing T cell receptors (TCRs) γ and TCR δ chains with diverse structural and functional heterogeneity. As a bridge between the innate and adaptive immune systems, γδ T cells participate in various immune responses during cancer progression. Because of their direct/indirect antitumor cytotoxicity and strong cytokine production ability, the use of γδ T cells in cancer immunotherapy has received a lot of attention over the past decade. Despite the promising potential of γδ T cells, the efficacy of γδ T cell immunotherapy is limited, with an average response ratio of only 21%. In addition, research over the past 2 years has shown that γδ T cells could also promote cancer progression by inhibiting antitumor responses, and enhancing cancer angiogenesis. As a result, γδ T cells have a dual effect and can therefore be considered as being both “friends” and “foes” of cancer. In order to solve the sub-optimal efficiency problem of γδ T cell immunotherapy, we review recent observations regarding the antitumor and protumor activities of major structural and functional subsets of human γδ T cells, describing how these subsets are activated and polarized, and how these events relate to subsequent effects in cancer immunity. A mixture of both antitumor or protumor γδ T cells used in adoptive immunotherapy, coupled with the fact that γδ T cells can be polarized from antitumor cells to protumor cells appear to be the likely reasons for the mild efficacy seen with γδ T cells. The future holds the promise of depleting the specific protumor γδ T cell subgroup before therapy, choosing multi-immunocyte adoptive therapy, modifying the cytokine balance in the cancer microenvironment, and using a combination of γδ T cells adoptive immunotherapy with immune checkpoint inhibitors.

Infertility is a common complication in diabetic men, mainly due to the loss of germ cells by apoptotic cell death. However, effective and safe approaches to prevent diabetic induction of testicular apoptosis for diabetic patients have not been available. Resveratrol (RSV), a group of compounds called polyphenols from plants, has been indicated its promising used clinically for cancers and cardiovascular diseases. Therefore, the present study aimed determining whether RSV attenuates type 1 diabetes (T1D)-induced testicular apoptotic cell death in a mouse model. We found that testicular apoptosis and oxidative stress levels were significantly higher in T1D mice than control mice. In addition, the phosphorylation level of metabolism-related Akt and GSK-3β was downregulated and Akt negative regulators PTEN, PTP1B and TRB3 were upregulated in the T1D group. These effects were partially prevented by RSV treatment. Nrf2 and its downstream genes, such as NQO-1, HO-1, SOD, catalase and metallothionein were significantly upregulated by RSV treatment. In addition, RSV-induced Nrf2 activation was found due to Keap1 degradation, mainly reliant on p62 that functions as an adaptor protein during autophagy. These results indicate that the attenuation of T1D-induced testicular oxidative stress and apoptosis by RSV treatment was mainly related to Akt-mediated Nrf2 activation via p62-dependent Keap1 degradation.

Purpose: The aberrantly upregulated Friend leukemia virus integration 1 (FLI1) is closely correlated with the malignant phenotype of small cell lung cancer (SCLC). This study attempts to examine if FLI1 exonic circular RNAs (FECRs) function as a new malignant driver that determines the metastatic phenotype in SCLC. Experimental Design: The expression of FECRs was examined in SCLC tissues and serum exosomes. The oncogenic activity of FECRs was investigated in SCLC cell lines and animal xenograft studies. Finally, we explored the molecular mechanisms underlying these non-coding RNAs as a malignant driver. Results: Therapeutic comparison of CRISPR Cas9 knockout and shRNA knockdown of FLI1 identified FECRs as a new non-canonical malignant driver in SCLC. We found that FECRs were aberrantly upregulated in SCLC tissues (p<0.0001), and was positively associated with lymph node metastasis (p<0.01). Notably, serum exosomal FECR1 was associated with poor survival and clinical response to chemotherapy. Silencing of FECRs significantly inhibited the migration in two highly aggressive SCLC cell lines and reduced tumor burden in a mouse xenograft model. Mechanistically, we uncovered that FECRs sequestered and subsequently inactivated tumor suppressor microRNA miR584-3p, leading to the activation of the Rho Associated Coiled-Coil Containing Protein Kinase 1 gene (ROCK1). Conclusion: This study identifies FLI1 exonic circular RNAs as a new oncogenic driver that promotes tumor metastasis through the miR584-ROCK1 pathway. Importantly, serum exosomal FECR1 may serve as a promising biomarker to track disease progression of SCLC.