Immunologic Research

Highlighting the role of CD44 in cervical cancer progression: immunotherapy’s potential in inhibiting metastasis and chemoresistance

AbstractCervical cancer affects thousands of women globally with recurring high-risk HPV infections being at the centre of cervical pathology. Oncological treatment strategies are continually challenged by both chemoresistance and metastasis within patients. Although both work hand-in-hand, targeting their individual mechanisms could prove highly beneficial for treatment outcomes. Such targets include the metastatic-promoting stem cell marker, CD44, which is abundant in cervical cancer cells and is common to both chemoresistance and metastatic mechanisms. Seeing that many existing advanced-stage cervical cancer treatment regimes, such as platinum-based chemotherapy regimens, remain limited and are rarely curative, alternative treatment options within the field of immunology are being considered. The use of immune checkpoint inhibition therapy, which targets immune checkpoints, CTLA-4 and PD-1/PD-L1, has shown promise as an alternate standard of care for patients suffering from advanced-stage cervical cancer. Therefore, this review aims to assess whether immune checkpoint inhibition can mitigate the pathological effects of CD44-induced EMT, metastasis, and chemoresistance in cervical cancer patients.

Lower expression of NINJ1 (Ninjurin 1), a mediator of plasma membrane rupture, is associated with advanced disease and worse prognosis in serous ovarian cancer

Gasdermin proteins (GSDMs) form pores in cell membranes upon various stimuli, leading to the release of certain proinflammatory molecules such as IL-1β and IL-18, and this ultimately results in pyroptotic cell death. NINJ1 (Ninjurin 1) has recently been identified as a cell membrane protein responsible for the final complete plasma membrane rupture following lytic cell death mechanisms including pyroptosis, causing the release of relatively larger molecules such as HMGB1 and LDH. In this study, we reported the presence of higher GSDMD and lower GSDME protein levels in ovarian tumors compared to surrounding non-malignant stroma in the tumor microenvironment. GSDME protein levels are also lower in the tumors of the omentum compared to adjacent stromal cells. We found that NINJ1 expression decreases from early to late stage in serous ovarian cancer, and the percentage of NINJ1 copy number loss events is the highest in ovarian cancer among other cancers. Moreover, we showed that low expression of NINJ1 is associated with shorter overall survival of patients with ovarian cancer. In support of the findings showing that low NINJ1 expression contributes to worse prognosis in this most lethal gynecological malignancy, NINJ1 expression was found to be lower in cisplatin-resistant ovarian cancer cells compared to cisplatin-sensitive counterparts in vitro. We suggest that the members of gasdermin family might have distinct functions in serous ovarian cancer, and low levels of NINJ1 might contribute, at least in part, to the progression and poorer prognosis of ovarian cancer. A complete picture of how pyroptosis and subsequent plasma membrane rupture are involved in ovarian cancer will be of high importance in order to identify actionable therapeutic vulnerabilities within this newly identified group of proteins.

Patients with radiation enteritis present regulatory T cell impairment associated with CTLA-4

Radiation enteritis is one of the most common side effects of ionizing radiation in patients with pelvic cancers. Increasing amounts of evidence indicate that pro-inflammatory responses significantly contribute to the development of radiation enteritis. In this study, we investigated the association between T regulatory (Treg) cells and the risk of developing radiation enteritis in cervical cancer patients. The following observations were made. First, the frequencies of CD25

Efficacy of chimeric antigen receptor natural killer cells in treatment of ovarian cancer. A meta-analysis of pre-clinical studies

Chimeric antigen receptor (CAR) therapies have expanded beyond T-cells with addition of natural killer (NK) cells. In ovarian cancer, long-term survival remains poor with the rising need for new therapies. Therefore, this meta-analysis evaluated the pre-clinical efficacy of emerging CAR-NK therapies in ovarian cancer models. Following PRISMA-guidelines and registered protocol (PROSPERO, CRD420251131530), literature from PubMed, Web of Science, and Scopus was retrieved till 30-06-2025 for pre-clinical in-vivo studies of CAR-NK therapy in ovarian cancer. Studies without in-vivo components or human CAR-NK were excluded. Primary outcomes were ratio of means (ROM) for tumor burden and median survival ratio (MSR). Data was analyzed in JASP™ and risk of bias (RoB) was determined using SYRCLE's RoB tool for animal studies. Fourteen experiments (21 CAR-NK groups) were included. CAR-NK significantly reduced tumor burden versus untreated controls (ROM 0.09 [0.03-0.32], p < 0.001) and unmodified/mock NK-cells (ROM 0.18 [0.08-0.42], p < 0.001). Survival was significantly prolonged (MSR 1.67 [1.31-2.14] vs. control; 1.40 [1.08-1.83] vs. unmodified/mock NK, both p < 0.05). Subgroup analyses revealed no significant modifiers, though trends favored mesothelin-targeted and NK-92-based CARs. Limited safety data indicated no cytokine release syndrome or graft-versus-host disease. Small sample size in subgroup analyses and unclear RoB in certain areas are some limitations of this study. However, the pooled estimates were robust to sensitivity analyses and relatively insignificant heterogeneity in survival outcomes could be important for poor long-term survival in ovarian cancers. CAR-NK demonstrates potential pre-clinical efficacy in ovarian cancer models, outperforming naive NK-cells with a consistent survival benefit.

Immunization with recombinant HPV16-E7d in fusion with Flagellin as a cancer vaccine: Effect of antigen-adjuvant orientation on the immune response pattern

Human papillomavirus (HPV) is the leading cause of cervical cancer worldwide. The pathogenesis of HPV is mainly dependent on its E7 and E6 proteins. Up to now, different adjuvants have been used to enhance the efficacy of the immune response against these two proteins. In this study, Flagellin (FLA) was used as adjuvant to test adjuvant activity and also see whether its orientation of attachment can affect the immune response pattern. The E7d-FLA and FLA-E7d in pET28a vector were constructed and then the recombinant proteins were expressed in E. coli BL21 (DE3) bacteria under IPTG induction. The expression of recombinant E7d-FLA and FLA-E7d proteins is confirmed by SDS-PAGE and western blot. Then, recombinant fusion proteins were purified using a nickel-nitrilotriacetic acid (Ni-NTA) column. The recombinant proteins were checked for endotoxin contamination and then quantified by Bradford. Eight-to-ten-week-old male Balb/C mice were immunized subcutaneously with 10 µg recombinant E7d-FLA, FLA-E7d and HPV16E7d vaccine on days 0, 14 and 28. In addition, PBS and FLA groups were considered as control group. Then, spleen cells were harvested to assess lymphocyte proliferation and IFN-γ, IL-4 and IL-17 cytokines. In addition, mice sera were used for specific total IgG and IgG1, IgG2a, IgG2b and IgM antibodies assessment by ELISA. The results show that E7d-FLA is more potent in the induction of lymphocyte proliferation, CTL response and specific total IgG, IgG2a and IgG2b response, while the FLA-E7d vaccine was associated with more IFN-γ, and IL-17 cytokine response. The results of this study proved the ability of FLA as an adjuvant in fusion with E7d in the induction of cellular and humoral immune responses. In addition, it also emphasizes that antigen-adjuvant orientation can affect the immune response strength and polarization against HPV E7d vaccine candidate. HIGHLIGHTS: Flagellin is attached to HPV-16 E7d at the C- or N-terminus to create E7d-FLA and FLA-E7d candidate vaccines. The E7d-FLA vaccine showed a significant increase in lymphocyte proliferation, CTL response and IgG response versus FLA-E7d vaccine. The FLA-E7d vaccine is associated with a significant increase in IFN-γ and IL-17 cytokines response versus E7d-FLA vaccine. It seems that that antigen-adjuvant orientation is an important parameter in the strength and polarization of immune response in HPV E7d vaccine candidate.