Immunophenotyping of Peripheral Blood Cells in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib.

Chronic lymphocytic leukemia (CLL) is a B-cell-derived hematologic malignancy whose progression depends on active B-cell receptor (BCR) signaling. Despite the spectacular efficacy of Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK), resistance can develop in CLL patients, and alternative therapeutic strategies are therefore required. Cancer immunotherapy has revolutionized cancer care and may be an attractive approach in this context. We speculated that characterizing the immune responses of CLL patients may highlight putative immunotherapeutic targets. Here, we used high-dimensional spectral flow cytometry to compare the distribution and phenotype of non-B-cell immune populations in the circulating blood of CLL patients treated with Ibrutinib displaying a complete response or secondary progression. Although no drastic changes were observed in the composition of their immune subsets, the Ibrutinib-resistant group showed increased cycling of CD8+ T cells, leading to their overabundance at the expense of dendritic cells. In addition, the expression of 11 different surface checkpoints was similar regardless of response status. Together, this suggests that CLL relapse upon Ibrutinib treatment may not lead to major alterations in the peripheral immune response.

Stiffness regulates dendritic cell and macrophage subtype development and increased stiffness induces a tumor-associated macrophage phenotype in cancer co-cultures.

Mechanical properties of tissues including their stiffness change throughout our lives, during both healthy development but also during chronic diseases like cancer. How changes to stiffness, occurring during cancer progression, impact leukocytes is unknown. To address this, myeloid phenotypes resulting from mono- and cancer co-cultures of primary murine and human myeloid cells on 2D and 3D hydrogels with varying stiffnesses were analyzed. On soft hydrogels, conventional DCs (cDCs) developed, whereas on stiff hydrogels plasmacytoid DCs (pDCs) developed. Soft substrates promoted T cell proliferation and activation, while phagocytosis was increased on stiffer substrates. Cell populations expressing macrophage markers CD14, Ly6C, and CD16 also increased on stiff hydrogels. In cancer co-cultures, CD86+ populations decreased on higher stiffnesses across four different cancer types. High stiffness also led to increased vascular endothelial growth factor A (VEGFA), matrix metalloproteinases (MMP) and CD206 expression; 'M2' markers expressed by tumor-associated macrophages (TAMs). Indeed, the majority of CD11c+ cells expressed CD206 across human cancer models. Targeting the PI3K/Akt pathway led to a decrease in CD206+ cells in murine cultures only, while human CD86+ cells increased. Increased stiffness in cancer could, thus, lead to the dysregulation of infiltrating myeloid cells and shift their phenotypes towards a M2-like TAM phenotype, thereby actively enabling tumor progression. Additionally, stiffness-dependent intracellular signaling appears extremely cell context-dependent, potentially contributing to the high failure rate of clinical trials.

M2 macrophages promote PD-L1 expression in triple-negative breast cancer via secreting CXCL1.

BACKGROUND: M2 macrophages are known to play a significant role in the progression of triple-negative breast cancer (TNBC) by creating an immunosuppressive microenvironment. The aim of this study is to investigate the impact of M2 macrophages on TNBC and their correlation with programmed death-ligand 1 (PD-L1) expression. METHODS: We employed a co-culture system to analyze the role of the mutual regulation of M2 macrophages and TNBC cells. Employing a multifaceted approach, including bioinformatics analysis, Western blotting, flow cytometry analysis, ELISA, qRT-PCR, lentivirus infection, mouse models, and IHC, we aimed to elucidate the influence and mechanism of M2 macrophages on PD-L1 expression. RESULTS: The results showed a substantial infiltration of M2 macrophages in TNBC tissue, which demonstrated a positive correlation with PD-L1 expression. CXCL1 exhibited abnormally high expression in M2 macrophages and enhanced the expression of PD-L1 in TNBC cells. Notably, silencing CXCL1 or its receptor CXCR2 inhibited M2 macrophages-induced expression of PD-L1. Mechanistically, CXCL1 derived from M2 macrophages binding to CXCR2 activated the PI3K/AKT/NF-κB signaling pathway, resulting in increased PD-L1 expression in TNBC. CONCLUSION: Broadly speaking, these results provide evidence for the immunosuppressive role of M2 macrophages and CXCL1 in TNBC cells, indicating their potential as therapeutic biomarkers.

Comprehensive analysis of the efficacy and safety of CAR T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia: a systematic review and meta-analysis.

BACKGROUND: Relapse/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL) represents paediatric cancer with a challenging prognosis. CAR T-cell treatment, considered an advanced treatment, remains controversial due to high relapse rates and adverse events. This study assessed the efficacy and safety of CAR T-cell therapy for r/r B-ALL. METHODS: The literature search was performed on four databases. Efficacy parameters included minimal residual disease negative complete remission (MRD-CR) and relapse rate (RR). Safety parameters constituted cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). RESULTS: Anti-CD22 showed superior efficacy with the highest MRD-CR event rate and lowest RR, compared to anti-CD19. Combining CAR T-cell therapy with haploidentical stem cell transplantation improved RR. Safety-wise, bispecific anti-CD19/22 had the lowest CRS rate, and anti-CD22 showed the fewest ICANS. Analysis of the costimulatory receptors showed that adding CD28ζ to anti-CD19 CAR T-cell demonstrated superior efficacy in reducing relapses with favorable safety profiles. CONCLUSION: Choosing a more efficacious and safer CAR T-cell treatment is crucial for improving overall survival in acute leukaemia. Beyond the promising anti-CD22 CAR T-cell, exploring costimulatory domains and new CD targets could enhance treatment effectiveness for r/r B-ALL.

Havoc in harmony: Unravelling the intricacies of angiogenesis orchestrated by the tumor microenvironment.

Cancer cells merely exist in isolation; rather, they exist in an intricate microenvironment composed of blood vessels, signalling molecules, immune cells, stroma, fibroblasts, and the ECM. The TME provides a setting that is favourable for the successful growth and survivance of tumors. Angiogenesis is a multifaceted process that is essential for the growth, invasion, and metastasis of tumors. TME can be visualized as a "concert hall," where various cellular and non-cellular factors perform in a "symphony" to orchestrate tumor angiogenesis and create "Havoc" instead of "Harmony". In this review, we comprehensively summarized the involvement of TME in regulating tumor angiogenesis. Especially, we have focused on immune cells and their secreted factors, inflammatory cytokines and chemokines, and their role in altering the TME. We have also deciphered the crosstalk among various cell types that further aids the process of tumor angiogenesis. Additionally, we have highlighted the limitations of existing anti-angiogenic therapy and discussed various potential strategies that could be used to overcome these challenges and improve the efficacy of anti-angiogenic therapy.

Immunoradiation Therapy for End-Stage Undifferentiated Cervical Cancer That Restored Sensitivity to Chemotherapy and Resulted in the Disappearance of the Cancer.

Among cervical cancers, small cell undifferentiated carcinoma is rare. Because of its rapid progression, the prognosis is extremely poor. During the course of cisplatin-based chemotherapy for stage Ⅳ small cell undifferentiated carcinoma of the cervix, the patient developed drug resistance, and standard treatment was no longer feasible. Therefore, immunoradiotherapy was administered to activate anticancer immunity. Surprisingly, the cancer drug sensitivity was restored, and cisplatin was again successful, and the cancer disappeared. In addition, the activation of cancer-specific immunity maintained the disappearance of the cancer. It should be noted that immunoradiotherapy not only increases anti-cancer immunity but may also contribute to overcoming cancer drug resistance.

Late-Stage Ovarian Cancer With Systemic Multiple Metastases Shows Marked Shrinkage Using a Combination of Wilms' Tumor Antigen 1 (WT1) Dendritic Cell Vaccine, Natural Killer (NK) Cell Therapy, and Nivolumab.

A patient with bilateral ovarian cancer, peritoneal dissemination, and multiple liver and lung metastases was found with a sudden accumulation of ascites six months after delivery. Chemotherapy was started, but the prognosis was judged to be poor, so immuno-cell therapy was combined with chemotherapy. After multiple cycles of Wilms' tumor antigen 1 (WT1) dendritic cell vaccine therapy and highly activated natural killer (NK) cell therapy, the patient showed a disappearance of ascites and a remarkable reduction of multiple cancers in the whole body. Furthermore, there were no side effects other than reactive fever caused by the administration of immune cells, and no damage to the patient's body was observed. This case suggests that not only the combined effects of chemotherapy and immunotherapy but also the combined use of various types of immuno-cell therapy may provide beneficial clinical effects in patients with extremely poor prognoses and few options for standard treatment.

Targeting MYC at the intersection between cancer metabolism and oncoimmunology.

MYC activation is a known hallmark of cancer as it governs the gene targets involved in various facets of cancer progression. Of interest, MYC governs oncometabolism through the interactions with its partners and cofactors, as well as cancer immunity via its gene targets. Recent investigations have taken interest in characterizing these interactions through multi-Omic approaches, to better understand the vastness of the MYC network. Of the several gene targets of MYC involved in either oncometabolism or oncoimmunology, few of them overlap in function. Prominent interactions have been observed with MYC and HIF-1α, in promoting glucose and glutamine metabolism and activation of antigen presentation on regulatory T cells, and its subsequent metabolic reprogramming. This review explores existing knowledge of the role of MYC in oncometabolism and oncoimmunology. It also unravels how MYC governs transcription and influences cellular metabolism to facilitate the induction of pro- or anti-tumoral immunity. Moreover, considering the significant roles MYC holds in cancer development, the present study discusses effective direct or indirect therapeutic strategies to combat MYC-driven cancer progression.

New-Onset Psoriasis Induced by Durvalumab.

Durvalumab is an immune checkpoint inhibitor (ICI) belonging to the anti-programmed death-ligand 1 (PD-L1) class, and it is used in the treatment of various end-stage malignancies. Immune checkpoint inhibitors are associated with various systemic and cutaneous adverse events. Psoriasiform drug eruptions have been clinically observed in patients who have a personal history of psoriasis being treated with ICIs. We present a unique case of de novo psoriasis in a patient being treated for poorly differentiated adenocarcinoma of the lung. The patient responded well to topical treatment and did not require discontinuation of durvalumab. Our case highlights the importance of clinician familiarity with psoriasis presentation, its association with durvalumab therapy, and treatment options for durvalumab-induced psoriasis.

Chronological interplay, clinical features, and treatments among patients with cancer and primary Sjögren's syndrome.

OBJECTIVE: While the incidence and type of blood malignancies are well documented amid primary Sjögren's syndrome patients (pSS), data focusing on solid neoplasms are more conflicting. We aimed to describe clinical, pathological, and immunological characteristics of pSS patients with cancers, along with the chronological interplay between the two conditions. METHODS: Outcomes concerning both pSS and cancer were retrospectively collected from Montpellier University Hospital (tertiary center) between 2019 and 2020. pSS characteristics were compared to a control group of pSS patients without cancer. RESULTS: A total of 165 patients with pSS were included: 55 patients with cancer (52 female, mean age 58.4 ± 10.4 years at pSS diagnosis; mean follow-up 10.5 ± 10.1 years, 12 patients had multiple cancers) and 110 controls without cancer. Characteristics of pSS patients with cancers were different from controls mostly for lymphoma prognosis factors. Among the 70 cancers, we recorded 55 solid neoplasms (whom 27 breast cancers and 8 lung cancers, and 82% of adenocarcinomas), with no evidence of disease at the end of follow-up in 85% of them. Among the 15 recorded blood malignancies, ten were lymphomas with an excellent prognosis. Regarding chronological interplay between cancer and pSS, most cancers (43%) were diagnosed close (± 5 years) to pSS diagnosis. Breast cancers were diagnosed before or close to pSS diagnosis (mean delay - 1.8 ± 13.0 years), at an early stage, with only two relapses (no cancer-related death), while lung cancers were diagnosed late after. CONCLUSIONS: The tight chronological interplay between breast cancer and pSS and the intriguing pathological and immunological pattern of pSS in these patients suggest a hypothesis of immune control of cancer.

Bioinformatics analysis and experimental validation identified HMGA2/microRNA-200c-3p/LSAMP/Wnt axis as an immunological factor of patients with colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignant cancers. The tumor microenvironment (TME) plays an important role in tumor progression and affects the prognosis of CRC patients. However, the TME has been poorly characterized and studies aiming to identify the biomarkers or combined risk scores of CRC patients are limited. Here, we overlapped differentially expressed genes and stromal/immune-score-related modules to identify immune- and stromal-related genes in CRC patients. These genes were fed into the LASSO-Cox regression analysis for dimensionality reduction to establish a TME-associated risk model. A high TME-associated risk score was identified as an unfavorable prognostic factor in The Cancer Genome Atlas and Gene Expression Omnibus datasets, as well as in a subgroup analysis, stratified by gender, age, microsatellite instability, and tumor lymph node metastasis stage. Ten genes were mutated more frequently in the high TME-associated risk score group; these mutations may be related to changes in the TME and the response to immunotherapy. Thus, a lower TME-associated risk score may indicate a better response to immunotherapy and longer overall survival. Experimental validation demonstrated that LSAMP, a novel TME-associated-risk-score-related gene, increased sensitivity of CRC to CD8+-T-cell-mediated cytotoxicity. A mechanistic investigation showed that the HMGA2/microRNA-200c-3p/LSAMP/Wnt axis was an immunological factor in CRC patients. To conclusion, we demonstrated that the TME-associated risk score model could be a reliable prognostic biomarker for CRC patients and highlighted the significance of the HMGA2/microRNA-200c-3p/LSAMP/Wnt axis in the oncoimmunology of CRC.

Androgen receptor agonist and antagonist reduce response of cytokine-induced killer cells on prostate cancer cells.

Despite many advances, prostate cancer (PCa) is still the second most frequently diagnosed cancer and fifth leading cause of cancer death in men worldwide. So far, the promising field of onco-immunology has not yet provided a satisfactory treatment option for PCa. Here we show that the ex vivo expansion and activation of cytokine-induced killer (CIK) cells isolated from primary peripheral blood mononuclear cells induce immune-mediated apoptosis in both human PCa LNCaP and C4-2 cells. Interestingly, pretreating LNCaP and C4-2 cells with either androgen or the androgen receptor (AR) antagonist enzalutamide mediates resistance to this immunogenic attack. This is associated with a reduction of both total cell loss and apoptosis levels suggesting one possible mechanism blunting onco-immunological activity. The data also suggest that secreted factors from AR ligand-treated PCa cell suppress lymphocyte proliferation. Further, we analysed immune-mediated killing activity using conditioned media from LNCaP and C4-2 treated cells. The obtained data suggest that the conditioned media from PCa treated cells does not influence a measurable lymphocyte-mediated apoptosis. However, analysing clonal expansion of activated lymphocytes, the androgen-derived conditioned media suppresses lymphocyte proliferation/expansion suggesting inhibition of onco-immunological activity by pretreatment of PCa cells with AR ligands.

Limbic Encephalitis With Dual Positivity.

Limbic encephalitis is a well-defined clinical disorder among paraneoplastic neurological syndromes. Although it is not always possible to identify specific autoantibodies in limbic encephalitis, the presence of anti-neuronal nuclear antibody type 1 (ANNA1 or anti-Hu), anti-Ma2, collapsin response mediator protein 5 (CRMP-5-IgG or anti-CV2), anti-GABAB receptors and anti-amphiphysin antibodies are often detected. A 66-year-old male patient with complaints of forgetfulness was evaluated in our clinic after having seizures. In the neurological examination, the patient was found to be confused. In cranial MR fluid-attenuated inversion recovery (FLAIR) and T2-weighted images, the right hippocampal and parahippocampal structures showed hyperintense areas complying with limbic encephalitis. He had improvement with a course of 2 g/kg intravenous immunoglobulin (IVIG) followed by high-dose methylprednisolone therapy. Following the high-dose methylprednisolone therapy, anti-PCA1 (Yo) and anti-amphiphysin antibodies were positive and the tissue pathology report confirmed combined small-cell carcinoma and large-cell neuroendocrine carcinoma of the lung. In recent years, paraneoplastic neurological syndromes are better recognized with the identification of specific antibodies and the ubiquitous information on pathogenesis. This is the first known report in the literature that a case with both positive anti-PCA1 (Yo) and anti-amphiphysin antibodies together and underlying small-cell and large-cell neuroendocrine carcinomas.

Uncovering transcriptomic landscape alterations of CAN-2409 in in vitro and in vivo glioma models.

Rationale: CAN-2409 is a locally delivered oncolytic therapy, which results in vaccination against the injected tumor. CAN-2409 consists of a non-replicating adenovirus armed with the Herpes virus thymidine kinase, which metabolizes ganciclovir into a phosphorylated nucleotide that is incorporated into the tumor cell's genome, thereby inflicting immunogenic cancer cell death. While CAN-2409's immunological impact has been well characterized, its effects on the tumor cells transcriptome remains unknown. We compared the transcriptomic landscape after treatment of glioblastoma models with CAN-2409 in vitro and in vivo to assess how the interplay with the tumor microenvironment influences CAN-2409-mediated transcriptome alterations. Methods: We performed RNA-Seq with CAN-2409 treated patient-derived glioma stem-like cells and tumors of C57/BL6 mice and compared KEGG pathway usage and differential gene expression focusing on immune cell and cytokine profiles. T-cell -killing assays were performed to assess candidate effectors. Results: PCA analysis showed distinct clustering of control and CAN-2409 samples under both conditions. KEGG pathway analysis revealed significant enrichment for p53 signaling and cell cycle pathway, with similar dynamics for key regulators of both pathways in vitro and in vivo, including MYC, CCNB1, PLK1 and CDC20. Selected alterations (PLK1 and CCNB1) were validated at the protein level. Cytokine expression analysis revealed upregulation of pro-inflammatory IL12a under both conditions; immune cell gene profiling showed reduction of myeloid associated genes. T-cell-killing assays showed increased killing in the presence of IL-12. Conclusion: CAN-2409 significantly alters the transcriptome both in vitro and in vivo. Comparison of pathway enrichment revealed mutual and differential utilization of pathways under both conditions, suggesting a modulating influence on the cell cycle in tumor cells, and of the tumor microenvironment on the transcriptome in vivo. IL-12 synthesis likely depends on interactions with the tumor microenvironment, and it facilitates CAN-2409 cell killing. This dataset provides potential to understand resistance mechanisms and identify potential biomarkers for future studies.

Reuniting philosophy and science to advance cancer research.

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer.

The immunoregulatory protein CD200 as a potentially lucrative yet elusive target for cancer therapy.

CD200 is an immunoregulatory cell surface ligand with proven pro-tumorigenic credentials via its ability to suppress CD200 receptor (CD200R)-expressing anti-tumor immune function. This definitive role for the CD200-CD200R axis in regulating an immunosuppressive tumor microenvironment has garnered increasing interest in CD200 as a candidate target for immune checkpoint inhibition therapy. However, while the CD200 blocking antibody samalizumab is still in the early stages of clinical testing, alternative mechanisms for the pro-tumorigenic role of CD200 have recently emerged that extend beyond direct suppression of anti-tumor T cell responses and, as such, may not be susceptible to CD200 antibody blockade. Herein, we will summarize the current understanding of CD200 expression and function in the tumor microenvironment as well as alternative strategies for potential neutralization of multiple CD200 mechanisms in human cancers.