Tissue-resident memory T cells play a key role in the efficacy of cancer vaccines.

Resident memory CD8+T cells (TRM) usually defined by the CD103 marker represent a new subset of long-lived memory T cells that remain in the tissues. We directly demonstrate their specific role in cancer vaccine-induced tumor regression. In human, they also seem to play a major role in tumor immunosurveillance.

[Cancer immunotherapy: Rational and recent breakthroughs]. / Immunothérapie des cancers : rationnel et avancées récentes.

Cancer immunotherapy has occupied a marginal therapeutic option in cancer despite strong arguments documenting the role of the immune system in controlling the proliferation of cancers. The recent success of immunotherapy results from a change in the past paradigm. From now on, the goal is not only to activate the immune system against tumor, but also to take account of the immunosuppressive tumor microenvironment Among these mechanisms, negative costimulatory molecules (CTLA-4, PD-1, etc.) expressed by T cells in the tumor could explain their lack of effectiveness in inhibiting tumor growth. Blocking these molecules allowed the reactivation of anti-tumor T cells. Clinically, the administration of anti-CTLA-4 antibody (ipilimumab: Yervoy®) was granted marketing authorization for patients with metastatic melanoma. The anti-PD-1 antibodies (nivolumab: Opdivo®, pembrolizumab: Keytruda®) have demonstrated clinical efficacy when compared to the standard therapy in metastatic melanomas, advanced lung cancers and metastatic renal cell carcinoma. In phase I and II clinical trials, other tumors (Hodgkin's disease, head and neck cancers, bladder cancer, gastric cancer, etc.) appear to be responsive to these immunomodulators. These treatments were associated with the occurrence of side effects dominated by autoimmunity predictable by unlocking the breaks exerted by immune system to maintain tolerance against self-antigen. The optimization of therapeutic combination based on these molecules and the search for biomarkers associated with these treatments constitute a challenge for the future for this new therapeutic class of drugs for oncology.

The G-protein on cholesterol-rich membrane microdomains mediates mucosal sensing of short- chain fatty acid and secretory response in rat colon.

AIM: Short-chain fatty acids (SCFA) stimulate colonic contraction and secretion, which are mediated by an enteric reflex via a mucosal sensing and cholinergic mechanisms. The involvement of G-protein signal transduction was examined in the secretory response to luminal propionate sensing in rat distal colon. METHODS: Mucosa-submucosa and mucosa preparations were used to measure short-circuit current (I(sc)) and acetylcholine (ACh) release respectively. Cholesterol-rich membrane microdomains, lipid rafts/caveolae, were fractionated using a sucrose gradient ultra-centrifugation after detergent-free extraction of the isolated colonic crypt. RESULTS: Luminal addition of methyl-ß-cyclodextrin (10 mm) and mastoparan (30 µm), lipid rafts/caveolae disruptors, significantly inhibited luminal propionate-induced (0.5 mm) increases in I(sc) , but did not affect increases in I(sc) induced by serosal ACh (0.05 mm) or electrical field stimulation (EFS). Luminal addition of YM-254890 (10 µm), a Gα(q/11) -selective inhibitor, markedly inhibited propionate-induced increase in I(sc) , but did not affect I(sc) responses to ACh and EFS. Both methyl-ß-cyclodextrin and YM-254890 significantly inhibited luminal propionate-induced non-neuronal release of ACh from colonocytes. Real-time PCR demonstrated that in mRNA expression of SCFA receptors, GPR 43 was far higher than that of GPR41 in the colon. Western blotting analysis revealed that the cholesterol-rich membrane microdomains that fractionated from colonic crypt cells were associated with caveolin-1, flotillin-1 and Gα(q/11) , but not GPR43. Uncoupling of Gα(q/11) from flotillin-1 in lipid rafts occurred under desensitization of the I(sc) response to propionate. CONCLUSIONS: These data demonstrate that the secretory response to luminal propionate in rat colon is mediated by G-protein on cholesterol-rich membrane microdomains, provably via Gα(q/11) .

Regulation of intestinal secretion involved in the interaction between neurotransmitters and prostaglandin E2.

In this short review, it will be described that neurotransmitter-induced secretion in the intestine may be influenced by the tissue level of prostaglandin E2 (PGE2). In the normal condition, vasoactive intestinal polypeptide (VIP) and acetylcholine (ACh) are the predominant neurotransmitters of secretomotor neurones. VIP and ACh activate distinct second messenger systems in epithelial cells, i.e. adenosine 3', 5'-cyclic monophosphate (cAMP) and calcium ion (Ca2+), respectively. An increase in intracellular cAMP induces a small amount of chloride (Cl-) secretion in epithelial cells, while simultaneous increases in intracellular Ca2+ and cAMP greatly enhances the cAMP-induced Cl- secretion. When the concentration of prostaglandins reaches a high level in the intestinal tissue substance P, which is a neurotransmitter of sensory neurones, can also induce a massive Cl- secretion by cross-potentiation of cAMP and Ca2+ in epithelial cells. In conclusion, it is considered that the concentration of tissue PGE2 may indicate tissue alert level, and when this level elevates, PGE2 enhances ACh and SP-induced Cl- secretion, thus mediating massive fluid secretion for host defence.

Inhibitory effect of natural and environmental estrogens on thymic hormone production in thymus epithelial cell culture.

The present study was carried out to assess the direct effect of natural estrogen and environmental estrogens on thymus epithelial cell (TEC) production/secretion of the thymic hormone thymosin-alpha 1 by using the technique of quantitative high-performance liquid chromatography. The presence of estrogen receptors in the TECs was also investigated. Murine TECs were cultured in the experimental DMEM medium containing various concentrations of natural or environmental estrogens, which was followed by determining the production of thymosin-alpha 1. The production of thymosin-alpha 1 by TECs was significantly inhibited by increasing concentrations of 17beta-estradiol (natural estrogen) over 3 x 10(-11) M, genistein (phytoestrogen) over 3 x 10(-9) M, coumestrol (phytoestrogen) over 3 x 10(-9) M, alpha-zearalanol (livestock anabolic) over 3 x 10(-7) and bisphenol-A (plastic) over 3 x 10(-6) M. Small amounts of estrogen receptor were present in the TECs. The above results clearly indicate that natural and environmental estrogens directly modulate TECs to produce thymic hormone probably through an estrogen receptor mechanism. Furthermore, our finding may be useful for evaluating biological effects of chemicals with estrogenic activity.

Low-grade malignant perineurioma of the paravertebral column, transforming into a high-grade malignancy.

A demarcated 6 x 5 cm right paravertebral tumor at the level of T6 in a 39-year-old male was removed surgically. Histologically, the tumor consisted of monomorphous benign-looking, low-cellular spindle cells embedded in desmoplastic stroma. Ten years later, the tumor recurred locally with metastasis to systemic organs, including the occipital skin. Malignancy was histologically evident by the increased cellularity, cellular atypia and mitotic activity. The patient died of respiratory failure at the age of 49. Retrospectively reviewed, the primary lesion was low-grade fibrosarcoma-like spindle cell tumor, with secondary transformation into a highly malignant form. The differential diagnoses included sclerosing epithelioid fibrosarcoma, low-grade fibromyxoid sarcoma and malignant peripheral nerve sheath tumor. Immunohistochemically, the spindle cells in the primary and recurrent tumors consistently expressed epithelial membrane antigen, vimentin, type 4 collagen and laminin. The tumor cells in the present case showed a differentiation toward perineurial cells, which are normally positive for these immunohistochemical markers. Hence, the appropriate diagnostic term should be 'malignant perineurioma', a subtype of malignant peripheral nerve sheath tumor.

Human immunodeficiency virus type 2 envelope glycoprotein binds to CD8 as well as to CD4 molecules on human T cells.

We report here that human immunodeficiency virus type 2 (HIV-2) envelope glycoprotein (gp105), but not HIV-1 gp120, can bind to CD8 molecules as well as to CD4 molecules on human T cells. This phenomenon may lead to differences in the life cycles of HIV-1 and HIV-2, and it may be related to the differences in disease manifestations of HIV-1 and HIV-2 infection, including longer survival of HIV-2-infected patients.

Identification of HTLV-1-specific CTL directed against synthetic and naturally processed peptides in HLA-B*3501 transgenic mice.

Previous studies of CTL responses to influenza peptides in HLA single transgenic mice resulted in the identification of at most one immunodominant epitope. Since HLA-B*3501 is known to present multiple HIV-1-specific T cell epitopes we tested the cellular immune response of HLA-B*3501 transgenic mice to synthetic HTLV-1 peptides mixed with the lipohexapeptide N-palmitoyl-S-[2,3-bis(palmitoyloxy)propyl]cysteinyl-seryl-lysyl-l ysyl- lysyl-lysine, which is a biocompatible, Th-epitopeindependent adjuvant. Eleven of 37 tested HLA-B*3501 binding peptides mounted a CTL response after three in vitro stimulations. The HLA-B*3501 affinity of peptides correlated with their ability to induce CTL in HLA-B*3501 transgenic mice. Seven peptides derived from env-gp46 (VPSPSSTPLL, VPSSSSTPL, YPSLALAPH, and YPSLALAPA), pol (QAFPQCTIL), gagp19 (YPGRVNEIL), and tax (GAFLTNVPY) proteins induced peptide-specific CTL Bulk CTL generated by four peptides derived from env-gp46 (SPPSTPLLY, VPSPSSTPLLY, and VPSPSSTPLL) and pol (QAFPQCTILQY) killed peptide-pulsed and recombinant vaccinia-infected target cells. The latter peptides therefore present T-cell epitopes and are vaccine candidates for our transgenic mouse model.

Clinical evaluation of prolonged chemotherapy combined with induction of hepatic drug-metabolizing enzymes as an adjuvant for treating patients with gastric cancer.

A clinical trial of a protracted adjuvant cancer chemotherapy was carried out on 207 patients with operable gastric cancer, from April, 1977, in the First Department of Surgery, Chiba University Hospital and two closely related hospitals. These patients were given intravenously 0.4 mg/kg and 0.2 mg/kg of mitomycin C on the day of operation and the next day, respectively, and then 16 mg/kg intravenously of Futraful (FT-207) daily from the 10th postoperative day until discharge, followed by oral administration of FT-207, 12 mg/kg, for 24 to 36 months after discharge. Two mg/kg of phenobarbital and 30 mg/kg of glutathione were administered randomly to half the number of patients (induction group) to induce hepatic drug-metabolizing enzymes. Significantly higher levels of serum 5-Fluorouracil (5-FU) released from FT-207 were found in the induction group than in the controls. Five-year overall survival rates in the induction and control groups revealed no difference. However, the survival rates in Stage III patients in the induction group were significantly superior in the 3-5 postoperative years, compared to those in the Stage III of the control group, while Stage I, II and IV patients apparently received no benefit from this induction treatment.

Intensified cancer themotherapy by induction of hepatic drug-metabolizing enzymes as a trial for the treatment for stomach cancer.

Studies of an intensified chemotherapy of FT-207, combined with MMC, have been under way since April 1977 in the First Department of Surgery of Chiba University Hospital and five closely related hospitals. These studies were performed on 114 patients with curative stomach cancer. The 114 patients received intravenously 0.4 mg/kg and 0.2 mg/kg of MMC on the operation day and the next day, respectively, and then intravenously 800 mg of FT-207 daily from the 10th postoperative day until discharge, followed by oral administration of FT-207, 600 mg, for more than 1 year after discharge. The 114 patients were divided into two groups. Half of the patients received 100 mg of phenobarbital and 30 mg/kg of glutathione for the purpose of induction of hepatic drug-metabolizing enzymes (induction group). Significantly higher levels of serum 5-FU released from FT-207 were observed in the patients of the induction group when compared to those of the control group. However, there was no statistically significant difference in survivals at both 12 and 24 months after operation between both groups.