Immune evasion by tumors includes several different mechanisms, including the inefficiency of antigen presenting cells (APCs) to trigger anti-tumor T cell responses. B lymphocytes may display a pro-tumoral role but can also be modulated to function as antigen presenting cells to T lymphocytes, capable of triggering anti-cancer immune responses. While dendritic cells, DCs, are the best APC population to activate naive T cells, DCs or their precursors, monocytes, are frequently modulated by tumors, displaying a tolerogenic phenotype in cancer patients. In patients with cervical cancer, we observed that monocyte derived DCs are tolerogenic, inhibiting allogeneic T cell activation compared to the same population obtained from patients with precursor lesions or cervicitis. In this work, we show that B lymphocytes from cervical cancer patients respond to treatment with sCD40L and IL-4 by increasing the CD80+CD86+ population, therefore potentially increasing their ability to activate T cells. To test if B lymphocytes could actually trigger anti-tumor T cell responses, we designed an experimental model where we harvested T and B lymphocytes, or dendritic cells, from tumor bearing donors, and after APC stimulation, transplanted them, together with T cells into RAG1-/- recipients, previously injected with tumor cells. We were able to show that anti-CD40 activated B lymphocytes could trigger secondary T cell responses, dependent on MHC-II expression. Moreover, we showed that dendritic cells were resistant to the anti-CD40 treatment and unable to stimulate anti-tumor responses. In summary, our results suggest that B lymphocytes may be used as a tool for immunotherapy against cancer.

Persistent infection with some types of mucosal human papillomavirus (HPV) is the etiological factor for the development of cervical cancer and its precursor lesions. Besides, several cofactors are known to play a role in cervical disease onset and progression either by favoring or by preventing HPV infection and persistence. The microbiome of a healthy female genital tract is characterized by the presence of 1 or few varieties of lactobacilli. However, high-throughput studies addressing the bacterial diversity and abundance in the female genital tract have shown that several factors, including hormonal levels, hygiene habits, and sexually transmitted diseases may disrupt the natural balance, favoring the outgrowth of some groups of bacteria, which in turn may favor some pathological states. Recently, the vaginal microbiome has emerged as a new variable that could greatly influence the natural history of HPV infections and their clinical impact. In this context, changes in the vaginal microbiome have been detected in women infected with HPV and women with HPV-associated lesions and cancer. However, the role of specific bacteria groups in the development/progression or prevention/regression of HPV-associated pathologies is not well understood. In this review we summarize the current knowledge concerning changes in vaginal microbiome and cervical disease. We discuss the potential functional interplay between specific bacterial groups and HPV infection outcomes.

Cervical cancer is the last stage of a series of molecular and cellular alterations initiated with Human Papillomavirus (HPV) infection. The process involves immune responses and evasion mechanisms, which culminates with tolerance toward tumor antigens. Our objective was to understand local and systemic changes in the interactions between HPV associated cervical lesions and the immune system as lesions progress to cancer. Locally, we observed higher cervical leukocyte infiltrate, reflected by the increase in the frequency of T lymphocytes, neutrophils and M2 macrophages, in cancer patients. We observed a strong negative correlation between the frequency of neutrophils and T cells in precursor and cancer samples, but not cervicitis. In 3D tumor cell cultures, neutrophils inhibited T cell activity, displayed longer viability and longer CD16 expression half-life than neat neutrophil cultures. Systemically, we observed higher plasma G-CSF concentration, higher frequency of immature low density neutrophils, and tolerogenic monocyte derived dendritic cells, MoDCs, also in cancer patients. Interestingly, there was a negative correlation between T cell activation by MoDCs and G-CSF concentration in the plasma. Our results indicate that neutrophils and G-CSF may be part of the immune escape mechanisms triggered by cervical cancer cells, locally and systemically, respectively.

Cervical cancer continues to be a public health problem in developing countries. Previous studies have shown that cervical cancer cells display markers of aerobic glycolysis, indicating that these tumors are likely to secrete lactate. Mostly, lactate is recognized as a molecule capable of suppressing immune responses, through inhibition of T cells, Mϕs, and dendritic cells. We and others have previously shown that Mϕs are frequent cells infiltrating cervical cancers with the ability to inhibit antitumor immune responses and promote tumor growth through angiogenesis. Here, we have tested the hypothesis that lactate, secreted by cervical cancer cells, can modulate Mϕ phenotype. First, we showed higher lactate plasma concentrations in patients with increasing cervical lesion grades, with maximum concentration in the plasma of cancer patients, which supported our hypothesis. We then inhibited lactate production in tumor cell spheroids established from cervical cancer derived cell lines, using the lactate dehydrogenase inhibitor, oxamate, prior to co‐culture with monocytes. Lactate mediated part of the crosstalk between tumor cells and Mϕs, promoting secretion of IL‐1β, IL‐10, IL‐6, and up‐regulation of hypoxia induced factor‐1α expression, and down‐regulation of p65‐NFκB phosphorylation in Mϕs. We also showed that Mϕs from co‐cultures treated with oxamate were better inducers of T cell activation. Of note, experiments performed with inhibition of the monocarboxylate transporters rendered similar results. Our data confirms the hypothesis that lactate, secreted by cervical tumor cells, influences the phenotype of tumor Mϕs, promoting a suppressive phenotype.

Background To determine whether age is a barrier against acceptability of cervicovaginal self-sampling in screening for cervical cancer at two gynecology outpatient clinics. Methods This is a cross-sectional study involving 116 women over 21 years of age with an abnormal Pap smear. Clinical and laboratorial data were recorded in electronic files. Women received detailed self-collection instructions. After the self-sampling procedure (Evalyn Brush®), women were instructed to answer a questionnaire about vaginal self-sampling acceptability that consisted of seven multiple-choice items. The participants were divided into three age brackets: 21 to 29 years, 30 to 49 years, and 50 years and over. Chi-square, Fischer exact, Kolmogorov-Smirnov and Kruskal-Wallis tests were used. Results The analysis of the participants’ perception of the procedure stratified according to age groups showed a decline in the fear of hurting oneself during the procedure as age increased. Most participants reported that it was very easy to understand how to use the self-sampling brush and that it was easy to use it. Most of them were neither embarrassed nor afraid of getting hurt during the procedure. The majority preferred self-sampling to collection by a healthcare professional. The main reason was practicality: the possibility of choosing the place and time for sampling. Conclusions The participating women found self-collection simple to understand and easy to accept regardless of age. The younger women indicated more fear and discomfort in self-sampling, which points to the need for attraction strategies that are more appealing to the younger generations.