Cancer Immunology Research

T and NK lymphocytes express CD137 (4-1BB), a costimulatory receptor of the TNFR family whose function is exploitable for cancer immunotherapy. Mitochondria regulate the function and survival of T lymphocytes. Herein, we show that CD137 costimulation provided by agonist mAb and CD137L (4-1BBL) induced mitochondria enlargement that resulted in enhanced mitochondrial mass and transmembrane potential in human and mouse CD8+ T cells. Such mitochondrial changes increased T-cell respiratory capacities and were critically dependent on mitochondrial fusion protein OPA-1 expression...

Peroxisome proliferator activated receptor-γ (PPARγ) is a lipid-activated nuclear receptor that promotes immune tolerance through effects on macrophages, dendritic cells (DCs), and regulatory T cells (Tregs). Granulocyte-macrophage colony stimulating factor (GM-CSF) induces PPARγ expression in multiple myeloid cell types. GM-CSF contributes to both immune tolerance and protection, but the role of PPARγ in these pathways is poorly understood. Here we reveal an unexpected stimulatory role for PPARγ in the generation of antitumor immunity with irradiated, GM-CSF-secreting tumor-cell vaccines (GVAX)...

Immunosuppressive myeloid-derived suppressive cells (MDSCs) are characterized by their phenotypic and functional heterogeneity. To better define their T cell-independent functions within the tumor, sorted monocytic CD14+CD11b+HLA-DRlow/- MDSCs (mMDSCs) from squamous cell carcinoma patients showed upregulated caspase-1 activity, that was associated with increased IL1 and IL18 expression. In vitro studies demonstrated that mMDSCs promoted caspase-1-dependent proliferation of multiple squamous carcinoma cell lines in both human and murine systems...

The clinical efficacy of T-cell therapies based on T cells transduced with genes encoding tumor-specific T-cell receptors (TCR-Ts) is related to the in vivo persistence of the T cells. To improve persistence without modifying TCR affinity, we instead modified intracellular signaling, using artificial T cell-activating adapter molecules (ATAMs), generated by inserting the intracellular domain (ICD) of activating T-cell signaling moieties into CD3ζ. ATAMs with the ICD of either CD28 or 4-1BB were generated, assembled into the TCR complex as a part of CD3ζ, and enhanced downstream signaling from the supramolecular activation cluster...

Somatic mutations can promote malignant transformation of airway epithelial cells, and induce inflammatory responses directed against resultant tumors. Tumor-infiltrating T lymphocytes (TILs) in early stage non-small cell lung cancer (NSCLC) secrete distinct pro-inflammatory cytokines, but the contribution of these TILs to tumor development and metastasis remains unknown. We show here that TILs in early stage NSCLC are biased toward IL17A expression (Th17) when compared to adjacent tumor-free tissue, whereas Th17 cells are decreased in tumor infiltrating loco-regional lymph nodes in advanced NSCLC...

Chronic lymphocytic leukemia cells can secrete immunoglobulin M. However, it is not clear whether secretory IgM (sIgM) plays a role in disease progression. We crossed the Eμ-TCL1 mouse model of CLL, in which the expression of human TCL1 oncogene was driven by the V(H) promoter-Ig(H)-Eμ enhancer, with MD4 mice whose B cells produced B cell receptor (membrane-bound IgM) and sIgM with specificity for hen egg lysozyme (HEL). CLL cells developed in these MD4/Eμ-TCL1 mice reactivated a parental Ig gene allele and secreted IgM, and did not recognize HEL...

With the rapidly expanding role of immune checkpoint inhibitor therapy in advanced cancer treatment, an increasing number of new immune-related adverse events (irAEs) are being reported. The present report describes sarcoid-like granulomatosis of the lung as a distinct type of irAE with characteristic clinical, imaging, and histologic features. In patients treated with immune checkpoint inhibitors, sarcoid-like granulomatosis of the lung presented with a focal area of consolidation in the lung, which was often nodular or round, in the absence of new or enlarging lymphadenopathy on imaging...

Triple-negative breast cancer (TNBC) is a leading cause of breast cancer death and is often associated with BRCA1 and BRCA2 mutation. Due to the lack of validated target molecules, no targeted therapy for TNBC is approved. Tissue factor (TF) is a common yet specific surface target receptor for cancer cells, tumor vascular endothelial cells and cancer stem cells in several types of solid cancers including breast cancer. Here we report evidence supporting the idea that TF is a surface target in TNBC. We used in vitro cancer lines and in vivo tumor xenografts in mice, all with BRCA1 or BRCA2 mutations, derived from patients' tumors...

Type I interferon (IFN-I) is a class of antiviral immunomodulatory cytokines involved in many stages of tumor initiation and progression. IFN-I acts directly on tumor cells to inhibit cell growth, and indirectly by activating immune cells to mount antitumor responses. To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in Her2/neu transgenic (neuT) mice carrying a nonfunctional mutation in the IFN-I receptor (IFNAR1). Such mice are unresponsive to this family of cytokines...

With the advancement of personalized cancer immunotherapies, new tools are needed to identify tumor antigens and evaluate T-cell responses in model systems, specifically those that exhibit clinically relevant tumor progression. Key transgenic mouse models of breast cancer are generated and maintained on the FVB genetic background, and one such model is the mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT) mouse - an immunocompetent transgenic mouse that exhibits spontaneous mammary tumor development and metastasis with high penetrance...

One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases, without toxicity to the normal GUCY2C-expressing intestinal epithelium, reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen...

Increased expression of co-inhibitory molecules such as PD-1 and Tim-3 on NK cells has been demonstrated in advanced cancer patients who harbor MHC class I-deficient tumors. However, even in preclinical models, the antitumor effects of checkpoint blockade on NK cells have not been clearly elucidated. Here, we show that anti-PD-1/anti-Tim-3 treatment suppressed tumor progression in mice bearing MHC class I-deficient tumors, and the suppression was further enhanced by recombinant IL21(rIL21) treatments through an NK cell-dependent mechanism...

Although tumor-associated macrophages (TAMs) display a M2-skewed tumor-promoting phenotype in most cancers, in colorectal cancer (CRC), both TAM polarization and its impact remain controversial. We investigated the role of the M2-polarizing p50 NF-κB subunit in orchestrating TAM phenotype, tumor microenvironment composition, and CRC progression. We first demonstrate, by parallel studies in colitis-associated cancer (CAC) and in genetically driven ApcMin mouse models, that the p50-dependent inhibition of M1-polarized gut inflammation supports CRC development...

Regulatory T cells (Treg) have long been considered one-sided suppressors of antitumor immune responses and hence associated with poor patient outcome in cancer. However, evidence is mounting of a paradoxical positive prognostic effect of Tregs on certain malignancies, including urinary bladder cancer (UBC). This discrepancy has partly been attributed to the shear misidentification of Tregs, but also to the inflammatory profile of the tumor. Our aim was to determine whether tumor-infiltrating Forkhead box P3+ (FOXP3+ ) cells confer a stable Treg phenotype and to investigate putative beneficial Treg functions, focusing on tumor-promoting inflammatory pathways in UBC...

T cells expressing chimeric antigen receptors (CARTs) have shown significant promise in clinical trials to treat hematologic malignancies, but their efficacy in solid tumors has been limited. Oncolytic viruses have the potential to act in synergy with immunotherapies due to their immunogenic oncolytic properties and the opportunity of incorporating therapeutic transgenes in their genomes. Here, we hypothesized that an oncolytic adenovirus armed with an EGFR-targeting, bispecific T-cell engager (OAd-BiTE) would improve the outcome of CART-cell therapy in solid tumors...

T cells genetically engineered with tumor antigen-specific T-cell receptor (TCR) genes have demonstrated therapeutic potential in patients with solid tumors. In order to achieve broader application, an efficient method to identify TCR genes for an array of tumor antigens and HLA restriction elements is required. Here, we have developed a method to construct a TCR-expression library from specimens, including frozen tumor biopsies, that contain antigen-specific T cells. TCR-expressing cassettes were constructed and cloned in a retroviral plasmid vector within 24 hours by unbiased PCR amplification of TCR α and β chain variable regions assembled with TCR constant regions...

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Immunotherapy, including the use of checkpoint inhibitors, is a potent therapeutic approach for some cancers, but has limited success with prostate tumors, in which immune suppression is instigated by the tumor. The immunosuppressive capacity of mast cells, which promote adenocarcinoma development in the prostate, prompted our investigation on whether mast cells promote tolerance to SV40 Large-T antigen, the transforming oncogene in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. The incidence of adenocarcinoma was reduced in the offspring of a cross between TRAMP mice and mast cell-deficient KitWsh mice...

CD16A is a potent cytotoxicity receptor on human NK cells, which can be exploited by therapeutic bispecific antibodies. So far, the effects of CD16A-mediated activation on NK cell effector functions beyond classical antibody-dependent cytotoxicity have remained poorly elucidated. Here, we investigated NK cell responses after exposure to therapeutic antibodies such as the tetravalent bispecific antibody AFM13 (CD30/CD16A), designed for the treatment of Hodgkin lymphoma and other CD30+ lymphomas. Our results reveal that CD16A engagement enhanced subsequent IL2 and IL15¬-driven NK cell proliferation and expansion...

AMD3100 (plerixafor), a CXCR4 antagonist, has been demonstrated to suppress tumor growth and modulate intratumoral T-cell trafficking. However, the effect of AMD3100 on immunomodulation remains elusive. Here, we explored immunomodulation and antitumor efficacy of AMD3100 in combination with a previously developed mesothelin-targeted, immune-activating fusion protein, VIC-008, in two syngeneic, orthotopic models of malignant mesothelioma (MM) in immunocompetent mice. We showed that combination therapy significantly suppressed tumor growth and prolonged animal survival in two mouse models...