Cancer Immunology Research

Transforming growth factor β (TGFβ) is an effector of immune suppression and contributes to a permissive tumor microenvironment that compromises effective immunotherapy. We identified a correlation between TGFB1 and genes expressed by myeloid cells, but not granulocytes, in TCGA lung adenocarcinoma data, in which high TGFB1 expression was associated with poor survival. To determine whether TGFβ affected cell fate decisions and lineage commitment, we studied primary cultures of CD14+ monocytes isolated from peripheral blood of healthy donors...

Complement aids in the construction of an immunosuppressive tumor microenvironment (TME). Tumor cell-derived C3 has been previously reported, but whether and how it acts on antitumor immunity remains to be elucidated. Here, we describe a mechanism for tumor cell-derived C3 in suppressing antitumor immunity. Tumor cell-derived C3 was activated intracellularly, which results in generation of C3a. C3a modulated tumor-associated macrophages (TAMs) via C3a-C3aR-PI3Kγ signaling, thereby repressing antitumor immunity...

Tumor-draining lymph nodes (TD-LNs) are the first site of metastasis of breast cancer (BC). Natural killer (NK) cells that infiltrate TD-LNs (including non-invaded (NI) or metastatic (M)-LNs from BC patients) and NK cells from healthy donor (HD)-LN were characterized, and their phenotype analyzed by flow cytometry. Low percentages of tumor cells invaded M-LNs, and these cells expressed ULBP2 and HLA class I molecules. Although NK cells from paired NI and M-LNs were similar, they expressed different markers compared to HD-LN NK cells...

Natural killer (NK) cells are primary immune cells that target cancer cells and can be used as a therapeutic agent against pancreatic cancer (PC). Despite their usefulness, NK-cell therapy is limited by tumor cell inhibition of NK-cell homing to tumor sites, thereby preventing a sustained antitumor immune response. One approach to successful cancer immunotherapy is to increase trafficking of NK cells to tumor tissues. Here, we developed an antibody-based NK cell-homing protein, named NK cell-recruiting protein-conjugated antibody (NRP-body)...

Tumor infiltration by immunosuppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs), causes resistance to immunotherapy. Semaphorin4D, originally characterized for its axonal guidance properties, also contributes to endothelial cell migration and survival and modulates global immune cytokine profiles and myeloid cell polarization within the tumor microenvironment. Here, we show how a therapeutic murine Sema4D mAb improves responses to immune checkpoint blockade in two murine carcinoma models...

Adoptive cellular therapy (ACT) using T-cell receptor (TCR)-engineered lymphocytes holds promise for eradication of disseminated tumors, but also an inherent risk of pathologic autoimmunity if targeted antigens or antigenic mimics are expressed by normal tissues. We evaluated whether modulating TCR affinity could allow CD8+ T cells to control tumor outgrowth without inducing concomitant autoimmunity in a preclinical murine model of ACT. RIP-mOVA mice express a membrane-bound form of chicken ovalbumin (mOVA) as a self-antigen in kidney and pancreas...

The BATF3-dependent cDC1 lineage of conventional dendritic cells (cDCs) is required for rejection of immunogenic sarcomas and for rejection of progressive sarcomas during checkpoint blockade therapy. One unique function of the cDC1 lineage is the efficient cross-presentation of tumor-derived neoantigens to CD8+ T cells, but it is not clear that this is the only unique function of cDC1 required for tumor rejection. We previously showed that BATF3 functions during cDC1 lineage commitment to maintain IRF8 expression in the specified cDC1 progenitor...

Antibodies that block the interaction between programmed death ligand 1 (PD-L1) and PD-1 have shown impressive responses in subgroups of cancer patients. PD-L1 expression in tumors seems to be a prerequisite for treatment response. However, it is heterogeneously expressed within tumor lesions and may change upon disease progression and treatment. Imaging of PD-L1 could aid in patient selection. Previously, we showed the feasibility to image PD-L1+ tumors in immunodeficient mice. However, PD-L1 is also expressed on immune cell subsets...

M2 polarization of macrophages is essential for their function in immunological tolerance, which might promote tumorigenesis. However, the molecular mechanism behind the polarization process is not fully understood. Given that several lines of evidence have suggested that long noncoding RNAs (lncRNAs) could be involved in regulating immune cell differentiation and function, the current study aimed to identify the lncRNAs that specifically modulate M2 macrophage polarization. By utilizing a series of cell-based M2 macrophage polarization models, a total of 25 lncRNAs with altered expression were documented based on lncRNA microarray-based profiling assays...

Anti-cancer immunotherapies demand optimal epitope targets, which could include proteasome-generated spliced peptides if tumor cells were to present them. Here, we show that spliced peptides are widely presented by MHC class I molecules of colon and breast carcinoma cell lines. The peptides derive from hot spots within antigens and enlarge the antigen coverage. Spliced peptides also represent a large number of antigens that would otherwise be neglected by patrolling T cells. These antigens tend to be long, hydrophobic, and basic...

Immune checkpoint inhibitors (ICIs) activate the immune system to assault cancer cells in a manner that is not antigen specific. We hypothesized that tolerance may also be broken to autoantigens, resulting in autoantibody formation, which could be associated with immune-related adverse events (irAEs) and antitumor efficacy. Twenty-three common clinical autoantibodies in pre- and post-treatment sera from 133 ipilimumab-treated melanoma patients were determined, and their development linked to the occurrence of irAEs, best overall response, and survival...

Mutated peptides (neoantigens) from a patient's cancer genome can serve as targets for T-cell immunity, but identifying which peptides can be presented by an MHC molecule and elicit T cells has been difficult. Although algorithms that predict MHC binding exist, they are not yet able to distinguish experimental differences in half-lives of the complexes (an immunologically relevant parameter, referred to here as kinetic stability). Improvement in determining actual neoantigen peptide/MHC stability could be important, as only a small fraction of peptides in most current vaccines are capable of eliciting CD8+ T-cell responses...

Many metastatic melanoma patients experience durable responses to anti-PD1 and/or anti-CTLA4, however, a significant proportion (over 50%) do not benefit from the therapies. In this study, we sought to assess pretreatment liquid biopsies for biomarkers that may correlate with response to checkpoint blockade. We measured the combinatorial diversity evenness of the T-cell receptor (TCR) repertoire (the DE50, with low values corresponding to more clonality and lack of TCR diversity) in pretreatment liquid biopsies from melanoma patients treated with anti-CTLA4 (n = 42) or anti-PD1 (n = 38) using a multi-N-plex PCR assay on genomic DNA (gDNA)...

Advances in single-cell biology have enabled measurements of >40 protein features on millions of immune cells within clinical samples. However, the data analysis steps following cell population identification are susceptible to bias, time-consuming, and challenging to compare across studies. Here, an ensemble of unsupervised tools was developed to evaluate four essential types of immune cell information, incorporate changes over time, and address diverse immune monitoring challenges. The four complementary properties characterized were: 1) systemic plasticity, 2) change in population abundance, 3) change in signature population features, and 4) novelty of cellular phenotype...

Preventive vaccination against tumor-associated endogenous antigens is considered to be an attractive strategy for the induction of a curative immune response concomitant with a long-lasting immunological memory. The mucin MUC1 is a promising tumor antigen, as its tumor-associated form differs from the glycoprotein form expressed on healthy cells. Due to aberrant glycosylation in tumor cells, the specific peptide epitopes in its backbone are accessible and can be bound by antibodies induced by vaccination. Breast cancer patients develop per se only low levels of T cells and antibodies recognizing tumor-associated MUC1 and clinical trials with tumor-associated MUC1 yielded unsatisfactory therapeutic effects indicating an urgent need to improve humoral immunity against this tumor entity...

Melanoma is an immunogenic neoplasm infiltrated by T cells, although these adaptive T cells usually fail to eradicate the tumor. Plasmacytoid dendritic cells (PDCs) are potent regulators of the adaptive immune response and can eliminate melanoma cells via TLR-mediated effector functions. The PDC compartment is maintained by progressively restricted bone marrow progenitors. Terminally differentiated PDCs exit the bone marrow into the circulation, then home to lymph nodes and inflamed peripheral tissues. Infiltration by PDCs is documented in various cancers...

Elucidation of the mechanisms of T cell-mediated antitumor responses will provide information for the rational design and development of cancer immunotherapies. Here, we found that calnexin, an endoplasmic reticulum (ER) chaperone protein, is significantly upregulated in oral squamous cell carcinoma (OSCC). Upregulation of its membranous expression on OSCC cells is associated with inhibited T-cell infiltration in tumor tissues and correlates with poor survival of OSCC patients. We found that calnexin inhibits the proliferation of CD4+ and CD8+ T cells isolated from the whole blood of healthy donors and OSCC patients and inhibits the secretion of IFNγ, TNFα, and IL2 from these cells...

Studies have pointed to a role of PARP1 in regulating gene expression through poly(ADP-ribosyl)ating, sequence-specific, DNA-binding transcription factors. However, few examples exist that link this role of PARP1 to the immunogenicity of cancer cells. Here, we report that PARP1 poly(ADP-ribosyl)ates STAT3 and subsequently promotes STAT3 de-phosphorylation, resulting in reduced transcriptional activity of STAT3 and expression of PD-L1. In this study, we showed that PARP1 silencing or pharmacological inhibition enhanced the transcription of PD-L1 in cancer cells, which was accompanied by the upregulation of PD-L1 protein expression, both in the cytoplasm and on the cell surface...

The immune microenvironment is crucial for epithelial ovarian cancer (EOC) progression and consists of tumor-associated macrophages (TAMs) and T lymphocytes, such as regulatory T cells (Tregs) and T helper 17 (Th17) cells. In this study, the Treg/Th17 ratio was significantly higher in EOC in situ and in metastatic peritoneal tissues than in benign ovarian tumors and benign peritoneum. The Treg/Th17 ratio was associated with histological grade and was an independent prognostic factor for overall survival of EOC patients...

NKG2D ligands are widely expressed in solid and hematologic malignancies but absent or poorly expressed on healthy tissues. We conducted a phase I dose-escalation study to evaluate the safety and feasibility of a single infusion of NKG2D-chimeric antigen receptor (CAR) T cells, without lymphodepleting conditioning in subjects with acute myeloid leukemia/myelodysplastic syndrome or relapsed/refractory multiple myeloma. Autologous T cells were transfected with a γ-retroviral vector encoding a CAR fusing human NKG2D with the CD3ζ signaling domain...