Cancer Immunology Research

Inhibitory immune checkpoint receptors (ICR), including programmed death 1 (PD-1) have been characterized as exhaustion markers on T cells that infiltrate the tumor microenvironment (TME) of many cancer types, including head and neck cancer (HNC). However, expression and function of ICRs, including PD-1, on natural killer (NK) cells remains less defined. NK cells are innate immune effector cells that lyse epidermal growth factor receptor (EGFR)-overexpressing HNC cells via cetuximab-mediated antibody-dependent cytotoxicity (ADCC)...

Checkpoint blockade therapy triggers tumor-specific immune responses in a variety of cancer types. We presumed that rectal cancer patients could have become sensitive to immunotherapy after receiving neoadjuvant chemoradiotherapy (nCRT). In this study, we report immune alternation in post-nCRT patients compared to pre-treatment conditions from GEO data. Whole exome sequencing of 14 locally advanced rectal cancer (LARC) patient samples showed that nCRT induced new mutations compared to the paired pre-treatment biopsies, evidenced by appearance of a neoantigen landscape...

Immune checkpoint inhibitor (ICI)-related diarrhea is attributed to inflammatory colitis, with no other drug-related differential diagnosis. Here, we investigated the occurrence of pancreatic atrophy (PA) in ICI-treated cancer patients and its correlation to exocrine pancreatic insufficiency (EPI). Metastatic melanoma, non-small cell lung carcinoma, and head & neck squamous cell carcinoma patients (n=403) treated with anti-PD-1 (n=356) or anti-CTLA-4 (n=47) were divided into a Case group (radiological evidence of PA), Control group matched by age, gender, and previous lines of treatment, and Colitis group (ICI-induced colitis)...

The immune composition of the tumor microenvironment regulates processes including angiogenesis, metastasis, and the response to drugs or immunotherapy. To facilitate the characterization of the immune component of tumors from transcriptomics data, a number of immune cell transcriptome signatures have been reported that are made up of lists of marker genes indicative of the presence a given immune cell population. The majority of these gene signatures have been defined through analysis of isolated blood cells...

Cancer-associated fibroblasts (CAFs) are generally associated with poor clinical outcome. CAFs support tumor growth in a variety of ways and can suppress antitumor immunity and response to immunotherapy. However, a precise understanding of CAF contributions to tumor growth and therapeutic response is lacking. Discrepancies in this field of study may stem from heterogeneity in composition and function of fibroblasts in the tumor microenvironment. Furthermore, it remains unclear whether CAFs directly interact with and suppress T cells...

We developed a screening assay in which luciferized ID8 expressing OVA was cocultured with transgenic CD8+ T cells specifically recognizing the model antigen in an H-2b-restricted manner. The assay was screened with a small-molecule library to identify compounds that inhibit or enhance T cell-mediated killing of tumor cells. Erlotinib, an EGFR inhibitor, was the top compound that enhanced T-cell killing of tumor cells. Subsequent experiments with erlotinib and additional EGFR inhibitors validated the screen results...

Natural killer cell (NKc)-based therapies offer promising outcomes in patients with tumors, but they could improve with appropriate selection of donors and optimization of methods to expand NKcs in vitro. Education through licensing interactions of inhibitory killer-cell immunoglobulin-like receptors (iKIR) and NKG2A with their cognate HLA class-I ligands optimizes NKc functional competence. This work has evaluated the role of licensing interactions in NKc differentiation and the survival of cancer patients...

Stromal cells of mesenchymal origin reside below the epithelial compartment and provide structural support in the intestine. These intestinal stromal cells interact with both the epithelial cell compartments, as well as infiltrating hematopoietic immune cells. The importance of these cells in regulating immune homeostasis during inflammation is well recognized. However, little is known about their function and phenotype in the inflammatory tumor microenvironment. Using a syngeneic, immunogenic model of colorectal cancer, we showed that TNFα-initiated inflammatory signaling in CT26 colorectal cancer cells selectively induced PD-L1 expression in stromal cells...

The presence of Fusobacterium nucleatum ( F. nucleatum ) in colorectal carcinoma tissue has been associated with microsatellite instability (MSI), lower-level T-cell infiltrates, and poor clinical outcomes. Considering differences in the tumor-immune microenvironment between MSI-high and non-MSI-high carcinomas, we hypothesized that the association of F. nucleatum with immune response might differ by tumor MSI status. Using samples from 1,041 rectal and colon cancer patients within the Nurses' Health Study and Health Professionals Follow-up Study, we measured F...

Although anti-PD-1 therapy has improved clinical outcomes for select patients with advanced cancer, many patients exhibit either primary or adaptive resistance to checkpoint inhibitor immunotherapy. The role of the tumor stroma in the development of these mechanisms of resistance to checkpoint inhibitors remains unclear. We demonstrated that pharmacologic inhibition of the TGFβ signaling pathway synergistically enhanced the efficacy of anti-CTLA-4 immunotherapy but failed to augment anti-PD-1/PD-L1 responses in an autochthonous model of BRAFV600E melanoma...

The heterogeneous expression of EGFRvIII [variant III mutant of epidermal growth factor receptor (EGFR)] in glioblastoma has significant impact on the clinical response to the treatment of EGFRvIII-specific chimeric antigen receptor-engineered T (CAR T) cells. We hypothesized that CAR T cells that could target both EGFRvIII and the form of EGFR expressed on tumor cells, but not EGFR on normal cells, would greatly improve efficacy without inducing on-target, off-tumor toxicity. Therefore, we developed a humanized single-chain antibody, M27, with a single specificity that binds to an epitope found both on wild-type EGFR- and EGFRvIII-overexpressing tumor cells, but not EGFR-expressing normal cells, including primary keratinocytes, on which wild-type EGFR is highly expressed...

Expression of T-cell checkpoint receptors can compromise antitumor immunity. Blockade of these receptors, notably PD-1 and LAG-3, which become expressed during T-cell activation with vaccination, can improve antitumor immunity. We evaluated whether T-cell checkpoint expression could be separated from T-cell activation in the context of innate immune stimulation with TLR agonists. We found that ligands for TLR1/2, TLR7, and TLR9 led to a decrease in expression of PD-1 on antigen-activated CD8+ T cells. These effects were mediated by IL12 released by professional antigen-presenting cells...

Macrophage recruitment is essential for tissue homeostasis but detrimental in most cancers. Tumor-associated macrophages (TAMs) play a key role in cancer progression. Controlling their migration is, thus, potentially therapeutic. It is assumed that macrophages use amoeboid motility in vivo like other leukocytes. However, it has not yet been explored. We examined TAM migration using intravital microscopy in mouse tumors and by monitoring ex vivo tissue infiltration in human surgical samples. We demonstrated that TAMs perform protease-dependent and ROCK-independent mesenchymal migration inside mouse fibrosarcoma and breast cancer explants using their own matrix metalloproteases (MMP)...

Myeloid-derived suppressor cells (MDSCs) are major regulators of immune responses in cancer. The differentiation and function of these MDSCs may be regulated through multiple factors such as microRNA(s). However, effect(s) of lncRNA on the differentiation and function of MDSCs is very little understood. We identify a novel long non-coding RNA (lncRNA) termed as Lnc-C/EBPβ in MDSCs, which may tightly control suppressive function of MDSCs. Lnc-C/EBPβ may be robustly induced in in vitro and in vivo tumor and inflammatory environments...

Although PD-1 blockade cancer immunotherapy has shown potential for a wide range of patients with cancer, its efficacy is limited, in part, due to the loss of effector cytotoxic T lymphocytes (CTLs) via terminal differentiation-induced apoptosis. We previously demonstrated that mitochondrial activation, by the agonists of peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1-α (PGC-1α)/transcription factor complexes, had synergistic effects with a PD-1-blocking monoclonal antibody in a mouse tumor model...

Mouse models have been instrumental in establishing fundamental principles of cancer initiation and progression and continue to be invaluable in the discovery and further development of cancer therapies. Nevertheless, important aspects of human disease are imperfectly approximated in mouse models, notably the involvement of endogenous retroviruses (ERVs). Replication-defective ERVs, present in both humans and mice, may affect tumor development and antitumor immunity through mechanisms not involving infection...

Metastatic breast cancer is a fatal disease that responds poorly to treatment. Cancer vaccines targeting antigens expressed by metastatic breast cancer cells and cancer stem cells could function as anticancer therapies. Cripto-1 is an oncofetal protein overexpressed in invasive breast cancer and cancer-initiating cells. In this study, we explored the potential of a Cripto-1-encoding DNA vaccine to target breast cancer in preclinical mouse models. BALB/c mice and BALB-neuT mice were treated with a DNA vaccine encoding mouse Cripto-1 (mCr-1)...

Treatment of patients bearing human papillomavirus (HPV)-related cancers with synthetic long-peptide (SLP) therapeutic vaccines has shown promising results in clinical trials against premalignant lesions, whereas responses against later stage carcinomas have remained elusive. We show that conjugation of a well-documented HPV-E7 SLP to ultra-small polymeric nanoparticles (NP) enhances the antitumor efficacy of therapeutic vaccination in different mouse models of HPV+ cancers. Immunization of TC-1 tumor-bearing mice with a single dose of NP-conjugated E7LP (NP-E7LP) generated a larger pool of E7-specific CD8+ T cells with increased effector functions than unconjugated free E7LP...

Immune-checkpoint blockade (ICB), in particular PD-1 inhibition, has rapidly changed the treatment landscape and altered therapeutic paradigms across many tumor types, with unprecedented rates of durable clinical responses in a number of cancers. Despite this success, only a subset of patients responds to ICB and, as a result, predictive biomarkers would be useful to guide the selection of patients for these therapies. This article highlights currently used biomarkers, as well as several promising novel candidates, and also discusses the challenges involved in establishing their analytic validity and clinical utility...

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