Oncoimmunology最新文献

Tissue-resident memory (T_RM) T cells have emerged as key players in cancer immunosurveillance, and their presence has been linked to a favorable clinical outcome in solid cancer patients. Liver metastases exhibit a highly immunosuppressive tumor microenvironment, however, the role and clinical impact of T_RM cell infiltration in colorectal cancer remain elusive. The expression of several tissue residency and activation biomarkers has been investigated on tumor-infiltrating lymphocytes isolated from 26 patients' colorectal cancer liver metastases (CRC liver metastases) and compared to 16 peripheral blood samples of patients with CRC liver metastases. Cytokine production was also evaluated in in vitro-activated T_RM and non-T_RM cells. The prognostic value of T_RM cells was also assessed in a well-defined cohort of CRC liver metastases. Here we identified two subsets of T_RM cells expressing CD103 and/or CD69 showing significantly higher expression of tissue residency and activation biomarkers. CD103⁺CD69⁺ T_RM cells subset showed almost exclusive expression of tumor reactivity biomarkers PD-1 and CD39. Supporting this observation, CD103⁺CD69⁺ T_RM cells showed a more oligoclonal TCR repertoire. Both T_RM subsets presented higher cytotoxic and functional capacity compared to non-T_RM cells. Our study shows that only the presence of CD103⁺CD69⁺ T_RM cells is associated with longer recurrence-free survival of colorectal cancer patients with liver metastases. Taken together, our work demonstrates the existence of a phenotypic heterogeneity of T_RM cells in colorectal cancer liver metastases. In this study, we identified a population of CD103⁺CD69⁺ T_RM cells exhibiting the characteristics of tumor reactivity and correlated with better patients' prognosis, with potential implications in optimal therapeutic strategies determination.

Locally advanced rectal cancer (LARC) is treated with neoadjuvant chemo-radiotherapy (nCRT) followed by surgery. A minority of patients show complete response (CR) to nCRT and may avoid surgery and its functional consequences. Instead, most patients show non-complete response (non-CR) and may benefit from additional treatments to increase CR rates. Reliable predictive markers are lacking. Aim of this study was to identify novel signatures predicting nCRT responsiveness. We performed a combined analysis of tumor-associated microbiome and immune gene expression profiling of diagnostic biopsies from 70 patients undergoing nCRT followed by rectal resection, including 16 with CR and 54 with non-CR. Findings were validated by an independent cohort of 49 patients, including 7 with CR and 42 with non-CR. Intratumoral microbiota significantly differed between CR and non-CR groups at genus and species level. Colonization by bacterial species of Ruminococcus genera was consistently associated with CR, whereas abundance of Fusobacterium, Porhpyromonas, and Oscillibacter species predicted non-CR. Immune gene profiling revealed a panel of 59 differentially expressed genes and significant upregulation of IFN-gamma and -alpha response in patients with CR. Integrated microbiome and immune gene profiling analysis unraveled clustering of microbial taxa with each other and with immune cell-related genes and allowed the identification of a combined signature correctly identifying non-CRS in both cohorts. Thus, combined intratumoral microbiome-immune profiling improves the prediction of response to nCRT. Correct identification of unresponsive patients and of bacteria promoting responsiveness might lead to innovative therapeutic approaches based on gut microbiota pre-conditioning to increase nCRT effectiveness in LARC.

Background: Human glioblastoma multiforme (GBM) is a highly aggressive tumor with insufficient therapies available. Especially, novel concepts of immune therapies fail due to a complex immunosuppressive microenvironment, high mutational rates, and inter-patient variations. The intratumoral heterogeneity is currently not sufficiently investigated.

Methods: Biopsies from six different locations were taken in a cohort of 16 GBM patients who underwent surgery. The tissue slides were analyzed utilizing high-content imaging microscopy and algorithm-based image quantification. Several immune markers for macrophage and microglia subpopulations were investigated. Flow cytometry was used to validate key results. Besides the surface marker, cytokines were measured and categorized based on their heterogenicity and overall expression.

Results: M2-like antigens, including CD204, CD163, Arg1, and CSF1R, showed comparatively higher expression, with GFAP displaying the least intratumoral heterogeneity. In contrast, anti-tumor-macrophage-like antigens, such as PSGL-1, CD16, CD68, and MHC-II, exhibited low overall expression and concurrent high intratumoral heterogeneity. CD16 and PSGL-1 were the most heterogeneous antigens. High expression levels were observed for cytokines IL-6, VEGF, and CCL-2. VILIP-a was revealed to differentiate most in principle component analysis. Cytokines with the lowest overall expression, such as TGF-β1, β-NGF, TNF-α, and TREM1, showed low intratumoral heterogeneity, in contrast to βNGF, TNF-α, and IL-18, which displayed high heterogeneity despite low expression.

Conclusion: The study showed high intratumoral heterogeneity in GBM, emphasizing the need for a more detailed understanding of the tumor microenvironment. The described findings could be essential for future personalized treatment strategies and the implementation of reliable diagnostics in GBM.

Macrophages are pivotal in driving breast tumor development, progression, and resistance to treatment, particularly in estrogen receptor-positive (ER+) tumors, where they infiltrate the tumor microenvironment (TME) influenced by cancer cell-secreted factors. By analyzing single-cell RNA sequencing data from 25 ER+ tumors, we elucidated interactions between cancer cells and macrophages, correlating macrophage density with epithelial cancer cell density. We identified that S100A11, a previously unexplored factor in macrophage-cancer crosstalk, predicts high macrophage density and poor outcomes in ER+ tumors. We found that recombinant S100A11 enhances macrophage infiltration and migration in a dose-dependent manner. Additionally, in a 3D matrix using a panel of three ER+ breast cancer cell lines, we showed that secreted S100A11 levels from cancer cells were associated with increased monocyte infiltration that subsequently differentiation toward macrophages. Genetic silencing of S100A11 in the S100A11-high T47D cancer cells reduced monocyte infiltration, consistent with results using a S100A11 blocking antibody in T47D cancer cells and in a clinically relevant patient-derived organoid model. Phenotypic analysis of macrophages cocultured with T47D cancer cells following S100A11 knockdown revealed lower expression of the immunosuppressive marker CD206, further underscoring the role of S100A11 as a paracrine regulator of pro-tumorigenic cancer-macrophage crosstalk. This study offers novel insights into the interplay between macrophages and cancer cells in ER+ breast tumors, highlighting S100A11 as a potential therapeutic target to modulate the macrophage-rich tumor microenvironment.

A recent in vitro study showed that pharmacological inhibition of the nuclear export receptor XPO1 suppresses oxaliplatin-induced nuclear release of HMGB1 and HMGB2, as well as the translocation of CALR to the plasma membrane. Moreover, cell-targeted-HMGB2 protein potently induced CALR exposure, even in the absence of oxaliplatin.

Cancer presents a significant public health concern, particularly in the context of metastatic disease. Surgical removal of primary tumors, while essential, can inadvertently heighten the risk of metastasis. Thus, there is a critical need for innovative neoadjuvant therapies capable of curtailing metastatic progression before or immediately following tumor resection. Addressing this imperative, the papaya mosaic virus nanoparticle (PapMV) has demonstrated potent immunostimulatory capabilities against both viruses and tumors, effectively hindering their proliferation. Our study reveals that PapMV exerts a protective effect against lung metastasis when administered systemically prior to tumor implantation or during the early stages of metastasis in various mouse models of cancer. This anti-tumor effect is initiated by the recruitment of myeloid cells in the lungs. These cells adopt a pro-inflammatory profile, secreting cytokines such as IFN-α, thus fostering a tumor microenvironment inhospitable to tumor progression. Crucially, this protective mechanism hinges on the presence of macrophages before treatment. TLR7 and IFN-I signaling pathways also play pivotal roles in this process. Furthermore, our findings demonstrate that PapMV triggers the activation of the bone marrow emergency response, which accounts for the influx of myeloid cells into the lungs. This study unveils a novel aspect of PapMV's functionality. By bolstering the immune system, PapMV confers robust protection against metastasis at an early stage of disease progression. This discovery holds promise for therapeutic intervention, particularly as a preemptive measure prior to or just after surgical intervention.

Breast cancer (BC) is a leading cause of death worldwide, particularly also among African woman. In order to better stratify patients for the most effective (immuno-) therapy, an in depth characterization of the immune status of BC patients is required. In this study, a cohort of 65 Ethiopian patients with primary BC underwent immune profiling by multicolor flow cytometry on peripheral blood samples collected prior to surgery and to any other therapy. Comparison with peripheral blood samples from healthy donors highlighted a general activation of the immune system, accompanied by the presence of exhausted CD4⁺ T cells and senescent CD8⁺ T cells with an inverted CD4/CD8 ratio in approximately 50% of BC cases. Enhanced frequencies of γδ T cells, myeloid-derived suppressor cells and regulatory T cells were also found. Correlation with clinical parameters demonstrated a progressive reduction in T cell frequencies with increasing histopathological grading of the tumor. Differences in CD8⁺ T cells and B cells were also noted among luminal and non-luminal BC subtypes. In conclusion, Ethiopian BC patients showed several alterations in the composition and activation status of the blood immune cell repertoire, which were phenotypically associated with immune suppression. The role of these immunological changes in the clinical outcome of patients with BC will have to be determined in follow-up studies and confirmed in additional patients' cohorts.

Colorectal cancer (CRC) is a multifaceted disease whose development and progression varies depending on tumor location, age of patients, infiltration of immune cells within cancer lesions, and the tumor microenvironment. These pathophysiological characteristics are additionally influenced by sex-related differences. The gut microbiome plays a role in initiation and progression of CRC, and shapes anti-tumor immune responses but how responsiveness of the immune system to the intestinal microbiota may contribute to sexual dimorphism of CRC is largely unknown. We studied survival, tumor-infiltrating immune cell populations and tumor-associated microbiome of a cohort of n = 184 male and female CRC patients through high-dimensional single-cell flow cytometry and 16S rRNA gene sequencing. We functionally tested the immune system-microbiome interactions in in-vivo and in-vitro models of the disease. High-dimensional single-cell flow cytometry showed that female patients are enriched by tumor-infiltrating invariant Natural Killer T (iNKT) cells but depleted by cytotoxic T lymphocytes. The enrichment of oral pathobionts and a reduction of β-glucuronidase activity are distinctive traits characterizing the gut microbiome of female patients affected by CRC. Functional assays using a collection of human primary iNKT cell lines demonstrated that the gut microbiota of female patients functionally impairs iNKT cell anti-tumor functions interfering with the granzyme-perforin cytotoxic pathway. Our results highlight a sex-dependent functional relationship between the gut microbiome, estrogen metabolism, and the decline of cytotoxic T cell responses, contributing to the sexual dimorphism observed in CRC patients with relevant implications for precision medicine and the design of targeted therapeutic approaches addressing sex bias in cancer.

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor characterized by poor prognosis and lack of effective treatments. In recent years, peptide vaccines that use sequences based on tumor-specific or tumor-associated antigens to activate immune responses against tumor cells have emerged as a new therapeutic strategy. In this study, we developed a novel therapeutic polypeptide vaccine targeting the tumor-associated antigen Fibrinogen-Like Protein 2 (FGL2), whose dominant epitope peptide was tandemly linked to the C-terminus of HCMV-IE1mut via a linker. We used this vaccine to compare the therapeutic efficacy of HCMV-IE1mut alone versus HCMV-IE1mut-FGL2_172-220 and investigate the potential mechanism of action of HCMV-IE1mut-FGL2_172-220 in glioma treatment. An in situ GBM model (GL261-IE1-luc cells) was used to determine the efficacy of the vaccine. Treatment with HCMV-IE1mut-FGL2_172-220 exerted antitumor effects and extended the survival of the GL261 animal model. We observed reduced proportions of microglia, regulatory T cells (Treg), and myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME) by immunofluorescence. Flow cytometry showed that compared to HCMV-IE1mut alone, treatment with HCMV-IE1mut-FGL2_172-220 increased the proportion of CD8+ T cells and tissue-resident memory T cells (TRM). ELISA analysis showed that it improved the secretion of tumor-specific IFN-γ and TNF-α by these cells and downregulated the expression of IL-6 and IL-10. Our study demonstrates that the long-peptide FGL2_172-220 improves the antitumor efficacy of HCMV-IE1mut, possibly by reshaping immune cells in the glioma microenvironment. These findings lay the groundwork for the development of therapeutic antigenic peptide vaccines to improve antitumor effects for cancer.

We recently demonstrated that a heterogeneous tumor irradiation strategy, combining high-dose and low-dose radiotherapy (RT) within the same tumor volume, can synergize with immunotherapy in mice. Our findings indicate that heterogeneous RT doses may promote the spatial diversification of the antitumor immune response. Spatial fractionation of the RT dose has the potential to enhance the therapeutic index of RT/IO combinations, particularly in scenarios where irradiating the entire tumor volume is unfeasible or excessively harmful to the patient.