Antibodies (Abs) and their fragments can be labeled with PET radioisotope (immunoPET) for in vivo diagnostic imaging. Compared to the conventional FDG-PET, immunoPET can be designed to target in vivo cancer-specific antigen expression levels for various tumors and metastasis, which makes immunoPET (iPET) a powerful technique for molecular imaging and therapy monitoring. However, achieving the optimal dose to minimize radioisotope toxicity without compromising the visualization of the smallest tumor is challenging. To find an ultra-minimal tracer dose, we have developed a novel iPET with an intact rituximab Ab labeled with 64Cu to image human CD20 (hCD20) in a transgenic mouse model for non-Hodgkin's lymphoma (NHL) imaging. Using phantom and in vivo mouse models, we optimized the minimal dose that can be administered in a mouse using a high-specific iPET tracer prepared from 64Cu-rituximab. A phantom study was used to characterize the scanner capability and limit for imaging using low doses. An ultra-minimal dose administered in a mouse model showed good image quality with high signal-to-noise ratio without compromising quantitative accuracy. The phantom study with below 50 μCi dose level indicated a slight increase in variability due to reduced dose specifically for target regions with lower uptakes (<3:1 ratio) relative to the background. In vivo study performed with four groups of mice (n = 3), each group injected with ~90, ~50, ~25, and ~10 μCi showed a linear increase of tracer uptake measured as percentage injected dose per gram (%ID/g). This tracer has shown high specific uptake in the spleen, where most B-cells are engineered to express hCD20. The study demonstrated that the lowest dose threshold limit for 64Cu-antibody-based iPET was about 25 μCi while achieving a high-quality image and quantitative accuracy.

Advanced colorectal cancer (CRC) continues to present with poor survival and treatment options remain limited. We have shown that increased activin A (activin) expression in the tumor microenvironment (TME) is associated with poor outcome in a cohort of stage III and IV CRC patients. Here, we hypothesized that activin promotes stage specific outcomes in CRC, enhancing metastasis and tolerance in late-stage CRC exclusively. We employed Digital Spatial Profiling (DSP) technology on a cohort of stage II and III CRC patient tissue samples obtained at the time of curative surgery to show that activin co-localization was associated with increased mitogenic signaling, proliferation, and immunosuppression in stage III, but not stage II, CRCs. Furthermore, we found strong linear correlations between markers of immunosuppression and signaling proteins in activin (+) areas, an effect that was not observed in activin (-) areas of tissue. Taken together these data suggest activin exerts pro-metastatic and immunosuppressive effects in stage III, but not stage II, CRC providing an attractive therapeutic target for advanced CRC.

This Special Issue is a collection of papers on skin cancers, focusing on their etiopathogenesis and the most innovative and effective therapies [...].

This review explores some of the complex mechanisms underlying antitumor T-cell response, with a specific focus on the balance and cross-talk between selected co-stimulatory and inhibitory pathways. The tumor microenvironment (TME) fosters both T-cell activation and exhaustion, a dual role influenced by the local presence of inhibitory immune checkpoints (ICs), which are exploited by cancer cells to evade immune surveillance. Recent advancements in IC blockade (ICB) therapies have transformed cancer treatment. However, only a fraction of patients respond favorably, highlighting the need for predictive biomarkers and combination therapies to overcome ICB resistance. A crucial aspect is represented by the complexity of the TME, which encompasses diverse cell types that either enhance or suppress immune responses. This review underscores the importance of identifying the most critical cross-talk between inhibitory and co-stimulatory molecules for developing approaches tailored to patient-specific molecular and immune profiles to maximize the therapeutic efficacy of IC inhibitors and enhance clinical outcomes.

Pyroptosis, driven by the N-terminal domain of gasdermin proteins (GSDM), promotes antitumor immunity by attracting lymphocytes to the tumor microenvironment (TME). However, current pyroptosis-inducing therapies like drug injections and phototherapy are limited to localized treatments, making them unsuitable for widespread or microscopic metastatic lesions. This study engineered oncolytic M1 viruses (rM1-mGSDME_FL and rM1-mGSDME_NT) to selectively deliver GSDME to tumor cells. These modified viruses enhanced tumor cell death in breast cancer models, suppressed tumor growth, extended survival in mice, and boosted immune cell infiltration, demonstrating significant anticancer potential through pyroptosis induction.

High-grade serious ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here, we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1α. We found that intratumoral neutrophils exhibited overactivation of ER stress response markers compared with their counterparts at non-tumor sites. Selective deletion of IRE1α in neutrophils delayed primary ovarian tumor growth and extended the survival of mice with HGSOC by enabling early T cell-mediated tumor control. Notably, loss of IRE1α in neutrophils sensitized tumor-bearing mice to PD-1 blockade, inducing HGSOC regression and long-term survival in ~ 50% of the treated hosts. Hence, neutrophil-intrinsic IRE1α facilitates early adaptive immune escape in HGSOC and targeting this ER stress sensor might be used to unleash endogenous and immunotherapy-elicited immunity that controls metastatic disease.

High-grade serous ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1α. We found that intratumoral neutrophils exhibited overactivation of ER stress response markers compared with their counterparts at non-tumor sites. Selective deletion of IRE1α in neutrophils delayed primary ovarian tumor growth and extended the survival of mice with HGSOC by enabling early T cell-mediated tumor control. Notably, loss of IRE1α in neutrophils sensitized tumor-bearing mice to PD-1 blockade, inducing HGSOC regression and long-term survival in ∼50% of treated hosts. Hence, neutrophil-intrinsic IRE1α facilitates early adaptive immune escape in HGSOC and targeting this ER stress sensor might be used to unleash endogenous and immunotherapy-elicited immunity that controls metastatic disease.

Immunotherapy has revolutionized the treatment of myeloid oncologic diseases, particularly for patients resistant to chemotherapy or ineligible for allogeneic stem cell transplantation due to age or fitness constraints. As our understanding of the immunopathogenesis of myeloid malignancies expands, so too do the treatment options available to patients. Immunotherapy in myeloid malignancies, however, faces numerous challenges due to the dynamic nature of the disease, immune dysregulation, and the development of immune evasion mechanisms. This review outlines the progress made in the field of immunotherapy for myeloid malignancies, addresses its challenges, and provides insights into future directions in the field.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) emerges as a key single-chain transmembrane glycoprotein predominantly expressed in effector T cells and regulatory T cells. It plays a crucial role in tumor immunity by modulating T cell responses. Specifically, CTLA-4 dampens T cell activation and proliferation while bolstering the survival of regulatory T cell through its competitive interaction with B7 family molecules, thereby aiding tumor cells in eluding immune detection. Given CTLA-4's significant influence on tumor immune dynamics, an array of anti-CTLA-4 antibody therapeutics have been clinically developed to combat various malignancies, including melanoma, renal cell carcinoma, colorectal carcinoma, hepatocellular carcinoma, non-small cell lung carcinoma, and pleural mesothelioma, demonstrating notable clinical therapeutic effects. This paper aims to delve into CTLA-4's integral role in tumor immunity and to encapsulate the latest advancements in the clinical research of anti-CTLA-4 antibody.

Bone is the most common site of breast cancer metastasis. Bone metastasis is incurable and is associated with severe morbidity. Utilizing an immunocompetent mouse model of spontaneous breast cancer bone metastasis, we profiled the immune transcriptome of bone metastatic lesions and peripheral bone marrow at distinct metastatic stages, revealing dynamic changes during the metastatic process. We show that cross-talk between granulocytes and T cells is central to shaping an immunosuppressive microenvironment. Specifically, we identified the PD-1 and TIGIT signaling axes and the proinflammatory cytokine IL1β as central players in the interactions between granulocytes and T cells. Targeting these pathways in vivo resulted in attenuated bone metastasis and improved survival, by reactivating antitumor immunity. Analysis of patient samples revealed that TIGIT and IL1β are prominent in human bone metastasis. Our findings suggest that cotargeting immunosuppressive granulocytes and dysfunctional T cells may be a promising novel therapeutic strategy to inhibit bone metastasis. Significance: Temporal transcriptome profiling of the immune microenvironment in breast cancer bone metastasis revealed key communication pathways between dysfunctional T cells and myeloid derived suppressor cells. Cotargeting of TIGIT and IL1β inhibited bone metastasis and improved survival. Validation in patient data implicated these targets as a novel promising approach to treat human bone metastasis.

Systemic immunotherapies have led to tremendous progress across the cancer landscape. However, several challenges exist, potentially limiting their efficacy in the treatment of solid tumors. Direct intratumoral injection can increase the therapeutic index of immunotherapies while overcoming many of the barriers associated with systemic administration, including limited bioavailability to tumors and potential systemic safety concerns. However, challenges remain, including the lack of standardized approaches for administration, issues relating to effective drug delivery, logistical hurdles, and safety concerns specific to this mode of administration. This article reviews the biologic rationale for the localized injection of immunotherapeutic agents into tumors. It also addresses the existing limitations and practical considerations for safe and effective implementation and provide recommendations for optimizing logistics and treatment workflows. It also highlights the critical role that radiologists, interventional radiologists, and medical physicists play in intratumoral immunotherapy with respect to target selection, image-guided administration, and response assessment.

Despite the exciting promise of cancer immunotherapy in the clinic, immune checkpoint blockade therapy and T cell-based therapies are often associated with low response rates, intrinsic and adaptive immune resistance, and systemic side effects. CRISPR-Cas-based genome editing appears to be an effective strategy to overcome these unmet clinical needs. As a safer delivery platform for the CRISPR-Cas system, non-viral nanoformulations have been recently explored to target tumor cells and immune cells, aiming to improve cancer immunotherapy on a gene level. In this review, we summarized the efforts of non-viral vector-based CRISPR-Cas-mediated genome editing in tumor cells and immune cells for cancer immunotherapy. Their design rationale and specific applications were highlighted.

Adenosine receptors are important in the normal physiological function of cells and the pathogenesis of various cancer cells, including breast cancer cells. The activity of adenosine receptors in cancer cells is related to cell proliferation, angiogenesis, metastasis, immune system evasion, and interference with apoptosis. Considering the different roles of adenosine receptors in cancer cells, we intend to investigate the function of adenosine receptors and their biological pathways in breast cancer to improve understanding of therapeutically relevant signaling pathways.

The presence of checkpoint markers in cancer cells aids in immune escape. The identification of checkpoint markers and early cancer markers is of utmost importance to gain clarity regarding the relationship between colitis and progressive inflammation leading to cancer. Herein, the gene expression levels of checkpoint makers, cancer-related pathways, and cancer genes in colon tissues of mouse models of chronic colitis (Winnie and Winnie-Prolapse mice) using next-generation sequencing are determined. Winnie mice are a result of a Muc2 missense mutation. The identification of such genes and their subsequent expression and role at the protein level would enable novel markers for the early diagnosis of cancer in IBD patients. The differentially expressed genes in the colonic transcriptome were analysed based on the Kyoto Encyclopedia of Genes and Genomes pathway. The expression of several oncogenes is associated with the severity of IBD, with Winnie-Prolapse mice expressing a large number of key genes associated with development of cancer. This research presents a number of new targets to evaluate for the development of biomarkers and therapeutics.

Cutaneous melanoma is the deadliest skin cancer. Most have Ras-MAPK pathway (BRAFV600E or NRAS) mutations and highly effective targeted therapies exist; however, they and immune therapies are limited by resistance, in part driven by small GTPase (Rho and Rac) activation. To facilitate preclinical studies of combination therapies to provide durable responses, we describe the first mouse melanoma lines resistant to BRAF inhibitors. Treatment of mouse lines, YUMM1.7 and YUMMER, with vemurafenib (Vem), the BRAFV600E-selective inhibitor, resulted in high-level resistance (IC50 shifts 20-30-fold). Resistant cells showed enhanced activation of Rho and the downstream transcriptional coactivator, myocardin-related transcription factor (MRTF). Resistant cells exhibited increased stress fibers, nuclear translocation of MRTF-A, and an increased MRTF-A gene signature. Pharmacological inhibition of the Rho/MRTF pathway using CCG-257081 reduced viability of resistant lines and enhanced sensitivity to Vem. Remarkably, co-treatment of parental lines with Vem and CCG-257081 eliminated resistant colony development. Resistant cells grew more slowly in vitro, but they developed highly aggressive tumors with a shortened survival of tumor-bearing mice. Increased expression of immune checkpoint inhibitor proteins (ICIs) in resistant lines may contribute to aggressive in vivo behavior. Here, we introduce the first drug-resistant mouse melanoma models for assessing combinations of targeted and immune therapies.

In cancer development and its clinical course, bacteria can be involved in etiology and secondary infection. Regarding etiology, various epidemiological studies have revealed that Helicobacter pylori can directly impact gastric carcinogenesis. The Helicobacter pylori-associated virulence factor cytotoxin-associated gene A perhaps plays an important role through different mechanisms such as aberrant DNA methylation, activation of nuclear factor kappa B, and modulation of the Wnt/β-catenin signaling pathway. Many other bacteria, including Salmonella and Pseudomonas, can also affect Wnt/β-catenin signaling. Although Helicobacter pylori is involved in both gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma, its role in the latter disease is more complicated. Among other bacterial species, Chlamydia is linked with a diverse range of diseases including cancers of different sites. The cellular organizations of Chlamydia are highly complex. Interestingly, Escherichia coli is believed to be associated with colon cancer development. Microorganisms such as Escherichia coli and Pseudomonas aeruginosa are frequently isolated from secondary infections in cancer patients. In these patients, the common sites of infection are the respiratory, gastrointestinal, and urinary tracts. There is an alarming rise in infections with multidrug-resistant bacteria and the scarcity of suitable antimicrobial agents adversely influences prognosis. Therefore, effective implementation of antimicrobial stewardship strategies is important in cancer patients.

Immune checkpoints are unique components of the body's defense mechanism that safeguard the body from immune responses that are potent enough to harm healthy body cells. When proteins present on the surface of T cells recognize and bind to the proteins present on other tumor cells, immune checkpoints are triggered. These proteins are called immunological checkpoints. The T cells receive an on/off signal when the checkpoints interact with companion proteins. This might avert the host's immune system from eliminating cancer cells. The standard care plan for the treatment of non-small cell lung cancer (NSCLC) has been revolutionized with the use of drugs targeting immune checkpoints, in particular programmed cell death protein 1. These drugs are now extended for their potential to manage SCLC. However, it is acknowledged that these drugs have specific immune related adverse effects. Herein, we discuss the use of immune checkpoint inhibitors in patients with NSCLC and SCLC, their outcomes, and future perspectives.

Inflammatory Bowel Disease (IBD) is a group of diseases that cause intestinal inflammation and lesions because of an abnormal immune response to host gut microflora. Corticosteroids, anti-inflammatories, and antibiotics are often used to reduce non-specific inflammation and relapse rates; however, such treatments are ineffective over time. Patients with chronic colitis are more susceptible to developing colorectal cancer, especially those with a longer duration of colitis. There is often a limit in using chemotherapy due to side effects, leading to reduced efficacy, leaving an urgent need to improve treatments and identify new therapeutic targets. Cancer immunotherapy has made significant advances in recent years and is mainly categorized as cancer vaccines, adoptive cellular immunotherapy, or immune checkpoint blockade therapies. Checkpoint markers are expressed on cancer cells to evade the immune system, and as a result checkpoint inhibitors have transformed cancer treatment in the last 5-10 years. Immune checkpoint inhibitors have produced long-lasting clinical responses in both single and combination therapies. Winnie mice are a viable model of spontaneous chronic colitis with immune responses like human IBD. Determining the expression levels of checkpoint markers in tissues from these mice will provide insights into disease initiation, progression, and cancer. Such information will lead to identification of novel checkpoint markers and the development of treatments with or without immune checkpoint inhibitors or vaccines to slow or stop disease progression.