The outstanding clinical success of immune checkpoint blockade has revived the interest in underlying mechanisms of the immune system that are capable of eliminating tumors even in advanced stages. In this scenario, CD4 and CD8 T cell responses are part of the cancer immune cycle and both populations significantly influence the clinical outcome. In general, the immune system has evolved several mechanisms to protect the host against cancer. Each of them has to be undermined or evaded during cancer development to enable tumor outgrowth. In this review, we give an overview of T lymphocyte-driven control of tumor growth and discuss the involved tumor-suppressive mechanisms of the immune system, such as senescence surveillance, cancer immunosurveillance, and cancer immunoediting with respect to recent clinical developments of immunotherapies. The main focus is on the currently existing knowledge about the CD4 and CD8 T lymphocyte interplay that mediates the control of tumor growth.
Gemcitabine administration after resection of pancreatic tumors in mice activates NK cell-mediated antitumor responses and inhibits local recurrence of tumors, consistent with observations from patients with PDAC. Transgenic mice with resectable pancreatic tumors might be promising tools to study adjuvant therapy strategies for patients.
BACKGROUND AND AIMS Programmed death 1 (PD‐1) checkpoint inhibition has shown promising results in patients with hepatocellular carcinoma, inducing objective responses in approximately 20% of treated patients. The roles of other coinhibitory molecules and their individual contributions to T‐cell dysfunction in liver cancer, however, remain largely elusive. APPROACH AND RESULTS We performed a comprehensive mRNA profiling of cluster of differentiation 8 (CD8) T cells in a murine model of autochthonous liver cancer by comparing the transcriptome of naive, functional effector, and exhausted, tumor‐specific CD8 T cells. Subsequently, we functionally validated the role of identified genes in T‐cell exhaustion. Our results reveal a unique transcriptome signature of exhausted T cells and demonstrate that up‐regulation of the inhibitory immune receptor T‐cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine‐based inhibitor motif domains (TIGIT) represents a hallmark in the process of T‐cell exhaustion in liver cancer. Compared to PD‐1, expression of TIGIT more reliably identified exhausted CD8 T cells at different stages of their differentiation. In combination with PD‐1 inhibition, targeting of TIGIT with antagonistic antibodies resulted in synergistic inhibition of liver cancer growth in immunocompetent mice. Finally, we demonstrate expression of TIGIT on tumor‐infiltrating CD8 T cells in tissue samples of patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma and identify two subsets of patients based on differential expression of TIGIT on tumor‐specific T cells. CONCLUSIONS Our transcriptome analysis provides a valuable resource for the identification of key pathways involved in T‐cell exhaustion in patients with liver cancer and identifies TIGIT as a potential target in checkpoint combination therapies.
Antagonistic antibodies targeting coinhibitory receptors have revolutionized the treatment of cancer by inducing durable immune responses and clinical remissions in patients. In contrast, success of agonistic costimulatory antibodies has thus far been limited because of the insufficient induction of adaptive immune responses. Here, we describe a novel vaccination method consisting of a primary dendritic cell (DC) immunization followed by a composite vaccination, including an agonistic CD40 antibody, soluble antigen, and a TLR3 agonist, referred to as CoAT. In mice, DC/CoAT prime-boost vaccinations targeting either MHC class I or II neoantigens or tumor-associated antigens rendered up to 60% of the total T-cell population specific for a single tumor epitope. DC/CoAT induced durable and complete remissions of large subcutaneous tumors without detectable side effects. Thus, booster vaccinations with agonistic costimulatory antibodies represent an ideal means to amplify DC vaccinations and induce robust T-cell immune responses while providing maximum flexibility regarding the choice of antigen. .
Immunotherapy of solid tumors is often hampered by the low frequency of tumor-specific T cells elicited by current vaccination strategies. Here, we describe a prime-boost vaccination protocol based on the administration of antigen conjugated to poly-lactic-co-glycolic acid (PLGA) microspheres followed by booster vaccination withEur. J. Immunol. 2014Immunol. . 44: 1213Immunol. -1224 carcinoma (HCC) is one of the most common solid cancers, ranking fifth in incidence worldwide and third in cancer-related deaths [1]. While early stages of hepatocellular carcinoma are subject to curative therapies including surgery, local therapy (radiofrequency ablation, ethanol injection), or orthotopic liver transplantation, therapy for advanced HCC is limited to palliative treatment options [2,3]. However, recent insight into the biology of hepatocellular carcinoma has revealed a well-orchestrated network of cell-mediated immunosuppression including T regs [4,5] and myeloid-derived suppressor cells [6] suggesting that HCC represents a potential targeted for immunotherapy. Most attempts to interfere with cancer immunosuppression or to prime HCC-specific T cells de novo, however, have had limited therapeutic effects [7]. The use of prime-boost protocols that involve the vaccination with viral or bacterial vectors is a potential way to overcome the limitations of current cancer vaccines. While these vectors are potent stimulators of polyfunctional T cells, they induce high levels of systemic inflammation and anti-vector immunity that prevents short interval prime-boost vaccination with homologous or heterologous vectors [8,9]. To circumvent this limitation of cancer vaccines, a novel vaccination protocol has been described recently that employs priming with cross-presented, poly-lactic-coglycolic acid (PLGA) microsphere-conjugated antigen that primes CD8 + T cells under conditions of low systemic inflammation. This noninflammatory priming regimen was followed by immunization with Listeria monocytogenes (LM), a gram-positive, facultative intracellular bacterial pathogen [8,10] that is currently used in clinical phase II trials for the treatment of cervical and pancreatic cancer [11]. In acute and chronic infections, the combined PLGA/LM vaccination protocol resulted in the generation of potent immune responses, was superior to priming with soluble peptide and protected against subsequent lethal challenges with pathogens [12,13]. Here, we describe a novel, inflammatory prime-boost vaccination, based on the injection of PLGA, antigen, and a TLR3 agonists followed by Listeria booster immunization, which induces massive CD8 + T-cell immune responses against solid tumors within two weeks. In models of both subcutaneous and orthotopic liver cancer, this modified vaccination protocol induced regression of established tumors and resulted in long-lasting protective CD8 + T-cell immune responses. We propose that PLGA-TLR3/LM prime-boost vaccinations represent a promising immunotherapeutic alternative to established dendritic cell tumor vacci...
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