DNA Damage and Repair Biomarkers of Immunotherapy Response. Cancer discovery DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies. Only a subset of patients respond to immune checkpoint blockade, and reliable predictive biomarkers of response are needed to guide therapy decisions. DNA repair deficiency is common among tumors, and emerging experimental and clinical evidence suggests that features of genomic instability are associated with response to immune-directed therapies. 10.1158/2159-8290.CD-17-0226

Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. Wei Spencer C,Duffy Colm R,Allison James P Cancer discovery Immune checkpoint blockade is able to induce durable responses across multiple types of cancer, which has enabled the oncology community to begin to envision potentially curative therapeutic approaches. However, the remarkable responses to immunotherapies are currently limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Indeed, an extraordinary amount of preclinical and clinical investigation is exploring the therapeutic potential of negative and positive costimulatory molecules. Insights into the underlying biological mechanisms and functions of these molecules have, however, lagged significantly behind. Such understanding will be essential for the rational design of next-generation immunotherapies. Here, we review the current state of our understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, and highlight conceptual gaps in knowledge. This review provides an overview of immune checkpoint blockade therapy from a basic biology and immunologic perspective for the cancer research community. 10.1158/2159-8290.CD-18-0367

SIRPα-CD47 Immune Checkpoint Blockade in Anticancer Therapy. Veillette André,Chen Jun Trends in immunology Inhibitory immune checkpoint blockade has been one of the most significant advances in anticancer therapy of the past decade. Research so far has largely focused on improving adaptive immune functions, but recent studies have indicated that the signal-regulatory protein (SIRP)α-CD47 pathway, a phagocytosis checkpoint in macrophages and other innate immune cells, may be an interesting therapeutic target. Here, we summarize current knowledge about SIRPα-CD47 blockade, and highlight key issues for future investigations. These include the targeting of prophagocytic receptors (Fc receptors or otherwise) to complement SIRPα-CD47 blockade, the understanding of constraints on phagocytosis other than the SIRPα-CD47 checkpoint and the contribution of immune cells other than macrophages. A better understanding of how SIRPα-CD47 blockade works may aid in identifying patients suitable for this therapy, avoiding potential toxicities and designing optimal combination therapies. 10.1016/j.it.2017.12.005

MTBHsp70-exFPR1-pulsed Dendritic Cells Enhance the Immune Response against Cervical Cancer. Cao Guangming,Cui Ran,Liu Chongdong,Zhang Guyu,Zhang Zhenyu Journal of Cancer Cervical cancer is the most common malignancy of the female reproductive system. Dendritic cell (DC)-based immunological therapy is a novel treatment for this cancer. DCs are specialized antigen-presenting cells (APCs) in the human immune system, and they can activate the T cells used in tumor immunological therapy. In this study, we developed a novel immunotherapeutic peptide by linking the (MTB) heat shock protein 70 (Hsp70) functional peptide to the extracellular domain of FPR1, a protein overexpressed in cervical cancer, to obtain an MTBHsp70-exFPR1 fusion protein. Our experiments confirmed that the MTBHsp70-exFPR1 protein could promote DC maturation and induce the secretion of IL-12p70, IL-1β, and TNF-α. The antitumor effect of human cytotoxic T lymphocytes (CTLs) activated by autologous DCs was assessed in NOG mice. These results indicate that DCs pulsed with MTBHsp70-exFPR1 can enhance antitumor immunity against cervical cancer, providing a novel immune therapeutic strategy. 10.7150/jca.29779

Killing cervical cancer cells by specific chimeric antigen receptor-modified T cells. He Yue,Li Xing-Ming,Yin Cheng-Hong,Wu Yu-Mei Journal of reproductive immunology The aim is to investigate the in vivo and in vitro killing effect of mesothelin chimeric antigen receptor T cells (MESO-CAR-T) in cervical squamous cell carcinoma. MESO-CAR-T cells were successfully constructed. In vitro verification of the killing effect of MESO-CAR-T cells was evaluated in the presence of SiHa cells by the lactate dehydrogenase release assay and cytokine release assay. The in vivo experiments were performed in immunodeficient NCG mice. After successful tumor formation with the subcutaneous implantation of SiHa cervical cancer cells, the injections of MESO-CAR-T cells into the tumors at different doses and frequencies were performed. Subsequently, the growth rate and size of the tumors in NCG mice were observed. A 17-fold increase in the number of MESO-CAR-T cells and a 16-fold increase in the number of Con-CAR-T cells were observed. The result of marker detection in the prepared MESO-CAR-T cells showed that CD3 T lymphocytes accounted for 97.0 % of all cells, indicating successful preparation of MESO-CAR-T cells. Expression of the membrane protein MESO was detected in 12.8 % of SiHa cells. When the ratio of MESO-CAR-T cells to SiHa cells was 20:1, the lysis of target cells was most significant and was observed in 22 % of the cells. In the presence of SiHa cells, the secretion of IL-4、IL-2、IL-5、TNF-α and IFN-γ in MESO-CAR-T cells was higher than that in the control group. The effect of two consecutive intratumoral injections of MESO-CAR-T cells was more obvious than that of one injection. The pharmacological effect of the injection was observed within 1 week. Our finding identified the certain in vivo and in vitro killing activity of MESO-CAR-T cells. 10.1016/j.jri.2020.103115