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Background Olfactory neuroblastoma is a rare malignancy of the anterior skull base typically treated with surgery and adjuvant radiation. Although outcomes are fair for low-grade disease, patients with high-grade, recurrent, or metastatic disease oftentimes respond poorly to standard treatment methods. We hypothesized that an in-depth evaluation of the olfactory neuroblastoma tumor immune microenvironment would identify mechanisms of immune evasion in high-grade olfactory neuroblastoma as well as rational targetable mechanisms for future translational immunotherapeutic approaches. Methods Multispectral immunofluorescence and RNAScope evaluation of the tumor immune microenvironment was performed on forty-seven clinically annotated olfactory neuroblastoma samples. A retrospective chart review was performed and clinical correlations assessed. Results A significant T cell infiltration was noted in olfactory neuroblastoma samples with a stromal predilection, presence of myeloid-derived suppressor cells, and sparse natural killer cells. A striking decrease was observed in MHC-I expression in high-grade olfactory neuroblastoma compared to low-grade disease, representing a mechanism of immune evasion in high-grade disease. Mechanistically, the immune effector stromal predilection appears driven by low tumor cell MHC class II (HLA-DR), CXCL9, and CXCL10 expression as those tumors with increased tumor cell expression of each of these mediators correlated with significant increases in T cell infiltration. Conclusion These data suggest that immunotherapeutic strategies that augment tumor cell expression of MHC class II, CXCL9, and CXCL10 may improve parenchymal trafficking of immune effector cells in olfactory neuroblastoma and augment immunotherapeutic responses.

BackgroundProstate cancer (PC) is the most frequently diagnosed cancer in men worldwide, making up 21% of all cancer cases. Although generally slow-growing, 370,000 men die from PC yearly. Immune checkpoint inhibitors (ICIs) are currently only indicated for the rare cases of microsatellite instability high or tumor mutation burden high disease. Combination therapy strategies that induce immune responses may expand the utility of ICIs. Here, we investigated the safety and efficacy of PROSTVAC, a therapeutic cancer vaccine that targets prostate-specific antigen (PSA), in combination with the programmed cell death protein-1 inhibitor nivolumab (NCT02933255).MethodsWe enrolled two cohorts in this trial (phase 1 and 2), both treated with PROSTVAC vaccine and nivolumab. The lead-in cohort had 12 patients with metastatic castration-resistant PC (mCRPC); the neoadjuvant cohort included 12 patients with localized PC who were candidates for radical prostatectomy (RP). We assessed tumor-infiltrating lymphocytes and programmed death-ligand 1 expression in matched formalin-fixed paraffin-embedded samples from baseline biopsies and RP samples. We measured changes in peripheral blood serum analytes, immune cell subsets and antigen-specific T cells targeting PSA, brachyury, and MUC-1 in both cohorts.ResultsIn the lead-in cohort, two patients had a prolonged complete radiographic response by Response Evaluation Criteria in Solid Tumors V.1.1. In the neoadjuvant cohort, CD4+ T helper cell and CD8+ T-cell densities were increased by >2-fold in RP samples compared with baseline in most patients (91% and 83% of patients, respectively). Proliferation of CD4+ and CD8+ T cells also increased in RP samples compared with baseline. Most patients from both cohorts (lead-in and neoadjuvant) had a >2-fold increase in PSA-specific (82% and 58%), MUC-1-specific (64% and 73%), and brachyury-specific (70% and 82%) T cells after therapy. In peripheral blood, we detected increases in proliferative CD4+ and CD8+ T cells but reductions in total CD4+ and CD8+ T cells.ConclusionNeoadjuvant PROSTVAC in combination with nivolumab is associated with increased intratumoral T-cell infiltrates, increased circulating tumor-associated antigen-specific T cells, and with radiographic and biochemical responses in the mCRPC setting. Our findings support the idea that the addition of a vaccine to a tumor-associated antigen might improve the clinical activity of immune checkpoint inhibition.Trial registration number NCT02933255.

BackgroundProstate cancer (PC) is the leading cause of cancer incidence among men in the US.1 For patients living with advanced PC, bone metastasis (mets) is a debilitating, yet common occurrence. As a result, bone mets are an acute source of pain, morbidity, and can contribute to patient mortality. To optimize immunotherapeutic strategies that target bone metastases, it is crucial to characterize their TIME.MethodsBone metastases tissue samples (n=13) were procured from 9 patients having castration resistant PC. For decalcification, we used EDTA to optimize bone tissue preservation and optimal proteomic analysis. Adjacent FFPE bone mets sections were immune-stained using 3 validated multiplex immunofluorescence panels and opal technology. We investigated the expression of HLA-DR on tumor cells. Furthermore we looked at densities oflymphocytes (T helpers, CD8+ T-cells and regulatory T-cells), tumor associated macrophages (M1 and M2), and myeloid-derived suppressor cells (M-MDSCs and PMN-MDSCs) infiltrating the bone mets. We utilized bone marrow tissue as a positive control.ResultsHLA-DR was found downregulated in all PC bone mets samples. The average CK+/HLA-DR+ ratio was approximately 16. HLA-DR downregulation is associated with T-cell immune escape. Additionally, CD4+ and CD8+ T-cell densities were relatively low in these samples (9 and 132 cells, respectively). Tumor associated macrophages were the most abundant immune cells found in these samples. M2-like macrophages (440) outnumbered M1-like macrophages (287), contributing to immunosuppression. . M2/CD8+ ratiowas 5.5. . Furthermore, PMN-MDSC and M-MDSC densities were 38 and 9, respectively.ConclusionsOur data confirm previous findings about the immune suppressed phenotypes within the TIME in prostate cancer bone mets.2 The down regulation of HLA-DR in tumor cells point to using NK cells as a future immunotherapy target. HLA-class I is still to be investigated in these samples. While tumor associated macrophages were the most abundant immune cells found within these samples, among the subtypes, M2-like macrophages were most prevalent. This suggests that rational and accurate design of therapeutics which relieve immunosuppression through M2 macrophage depletion, or M1 macrophage repolarization, may help combat PC bone mets.ReferencesSiegel R, Miller K, Wagle N, Jemal A. Cancer statistics, 2023. CA: A Cancer Journal for Clinicians. 2023;73:17–48.Stultz J, Fong L. Prostate Cancer and Prostatic Diseases. Prostate Cancer Prostatic Dis. 2021;24:697–717.Ethics ApprovalThis study obtained ethics approval by Thomas Jefferson University IRB. Patients provided informed consent prior to participating in this study.

BackgroundProstate cancer is the most diagnosed cancer in men worldwide, making up 21% of all cancer cases.1 Although this disease is slow growing, 370,000 men die from prostate cancer every year. Prostate cancer is mostly a cold tumor, lacking infiltrating immune cells.2 To switch the tumor immune microenvironment phenotype from cold to inflamed we used Prostvac, a therapeutic cancer vaccine that targets prostate-specific antigen (PSA) in monotherapy and in combination with Nivolumab, a PD1 inhibitor.MethodsPatients with localized prostate cancer were enrolled in 2 distinct clinical trials. In the 1st trial, patients received subcutaneously neoadjuvant Prostvac vaccine alone for 4 doses (NCT02153918). In the 2nd trial, patients received Prostvac and Nivolumab (NCT 02933255).We studied the T cells infiltration in matched paired samples from pre-treatment biopsies and post-treatment Radical prostatectomy from patients enrolled in these trials (26 patients had monotherapy and 12 patients had combination therapy). Using multiplex immunofluorescence technique and opals, we immune-stained formalin fixed paraffin-embedded sections with a validated lymphocyte panel of markers that included DAPI, CD4, CD8, FOXP3, Ki67, Pan CK and PD-L1. We analyzed the data by measuring the cell densities in Invasive margin, center of the tumor and normal regions.ResultsIn both trials and using Prostvac alone or in combination with Nivolumab, CD4 and CD8 T cells increased in the overall prostate tumor tissues, the invasive margins and the center of the tumors. These increases are more predominant and frequent in patients who received Prostvac and Nivolumab. CD4 and CD8 densities increased by at least 2-fold in 91% and 83%, respectively and in patients who received the combination therapy, whereas this increase was found in 71% and 58% in patients who received only the vaccine. Ki67 was found higher in CD8 T-cells (Mean from 2.9 cells/mm2 to 4.16 cells/mm2, p=0.09) and significantly higher in CD4 T-cells in the overall tissues (Mean from 7.63 cells/mm2 to 15.68 cells/mm2, p=0.0019) only after the combination treatment, suggesting a role of blocking PD1 in activating these lymphocytes. T-regulatory T cells were found low in all samples (average of 10 cells/mm2).ConclusionsImmunotherapy is standard therapy for many tumors, however PD-1 inhibitors as single agents have no clinical role in prostate cancer outside MSI high cancer. Combination immunotherapies could change the tumor immune-microenvironment landscape and enhance immune response by increasing T-cells activation and infiltration and therefore overcoming tumor immune evasion.Trial RegistrationNCT: 02153918 and NCT: 02933255ReferencesSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209−249.Yarchoan, M., Johnson, B., Lutz, E. et al. Targeting neoantigens to augment antitumour immunity. Nat Rev Cancer 2017; 17:209–222.Ethics ApprovalThe study obtained ethics approval by NIH IRB. All participants gave informed consent before taking part in these trials.

Multiplex staining enables simultaneous detection of multiple protein markers within a tissue sample. However, the increased marker count increased the likelihood of staining and imaging failure, leading to higher resource usage in multiplex staining and imaging. We address this by proposing a deep learning-based MArker imputation model for multipleX IMages (MAXIM) that accurately impute protein markers by leveraging latent biological relationships between markers. The model's imputation ability is extensively evaluated at pixel and cell levels across various cancer types. Additionally, we present a comparison between imputed and actual marker images within the context of a downstream cell classification task. The MAXIM model's interpretability is enhanced by gaining insights into the contribution of individual markers in the imputation process. In practice, MAXIM can reduce the cost and time of multiplex staining and image acquisition by accurately imputing protein markers affected by staining issues.Competing Interest StatementThe authors have declared no competing interest.Footnotes* https://github.com/mahmoodlab/MAXIM