The introduction of immune-checkpoint blockade in the cancer therapy led to a paradigm change of the management of late stage cancers. There are already multiple FDA approved checkpoint inhibitors and many other agent...The introduction of immune-checkpoint blockade in the cancer therapy led to a paradigm change of the management of late stage cancers. There are already multiple FDA approved checkpoint inhibitors and many other agents are undergoing phase 2 and early phase 3 clinical trials. The therapeutic indication of immune checkpoint inhibitors expanded in the last years, but still remains unclear who can benefit. Micro RNAs are small RNAs with no coding potential. By complementary pairing to the 3' untranslated region of messenger RNA, microRNAs exert posttranscriptional control of protein expression. A network of microRNAs directly and indirectly controls the expression of checkpoint receptors and several microRNAs can target multiple checkpoint molecules,mimicking the therapeutic effect of a combined immune checkpoint blockade. In this review, we will describe the microRNAs that control the expression of immune checkpoints and we will present four specific issues of the immune checkpoint therapy in cancer:(1) imprecise therapeutic indication,(2) difficult response evaluation,(3) numerous immunologic adverse-events, and(4)the absence of response to immune therapy. Finally, we propose microRNAs as possible solutions for these pitfalls. We consider that in the near future microRNAs could become important therapeutic partners of the immune checkpoint therapy.展开更多
Antigen-specific CD8＋T cells play a critical role in eradicating transformed or virally infected cells. Upon recognition of cancerous or viral originated peptides, presented by antigen-presenting cells （APCs） in th...Antigen-specific CD8＋T cells play a critical role in eradicating transformed or virally infected cells. Upon recognition of cancerous or viral originated peptides, presented by antigen-presenting cells （APCs） in the form of peptide-MHC class I complex, CD8＋T cells become activated, rapidly and extensively proliferate and differentiate into functionally competent effector cells. Following successfully and timely clearing transformed or virally infected cells, the majority of effector CD8＋Tcells die of apoptosis. Concomitantly a small fraction （around 5%-10%） of effector CD8＋T cells survive and progressively differentiate into long-lived and self-renewable memory CD8＋T cells.展开更多
基金supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination(OSC)the NIH/NCI grant 1 R01 CA182905-01+6 种基金a U54 grant-UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Projecta Team DOD (Grant No.CA160445P1) granta Ladies Leukemia League granta CLL Moonshot Flagship projecta SINF 2017 grantthe Estate of C.G.Johnson,Jr.supported by a POC grant, entitled "Clinical and economical impact of personalized targeted anti-microRNA therapies in reconverting lung cancer chemoresistance"-CANTEMIR, Competitively Operational Program, 2014-2020, Grant No.35/01.09.2016,My SMIS 103375
文摘The introduction of immune-checkpoint blockade in the cancer therapy led to a paradigm change of the management of late stage cancers. There are already multiple FDA approved checkpoint inhibitors and many other agents are undergoing phase 2 and early phase 3 clinical trials. The therapeutic indication of immune checkpoint inhibitors expanded in the last years, but still remains unclear who can benefit. Micro RNAs are small RNAs with no coding potential. By complementary pairing to the 3' untranslated region of messenger RNA, microRNAs exert posttranscriptional control of protein expression. A network of microRNAs directly and indirectly controls the expression of checkpoint receptors and several microRNAs can target multiple checkpoint molecules,mimicking the therapeutic effect of a combined immune checkpoint blockade. In this review, we will describe the microRNAs that control the expression of immune checkpoints and we will present four specific issues of the immune checkpoint therapy in cancer:(1) imprecise therapeutic indication,(2) difficult response evaluation,(3) numerous immunologic adverse-events, and(4)the absence of response to immune therapy. Finally, we propose microRNAs as possible solutions for these pitfalls. We consider that in the near future microRNAs could become important therapeutic partners of the immune checkpoint therapy.
文摘Antigen-specific CD8＋T cells play a critical role in eradicating transformed or virally infected cells. Upon recognition of cancerous or viral originated peptides, presented by antigen-presenting cells （APCs） in the form of peptide-MHC class I complex, CD8＋T cells become activated, rapidly and extensively proliferate and differentiate into functionally competent effector cells. Following successfully and timely clearing transformed or virally infected cells, the majority of effector CD8＋Tcells die of apoptosis. Concomitantly a small fraction （around 5%-10%） of effector CD8＋T cells survive and progressively differentiate into long-lived and self-renewable memory CD8＋T cells.
