Thibault Voron

VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors

VEGF-A production in the tumor microenvironment enhances expression of PD-1 and other inhibitory checkpoints involved with CD8+ T cell exhaustion, which can be reversed with anti-VEGF/VEGFR treatment.

Control of the Immune Response by Pro-Angiogenic Factors

The progressive conversion of normal cells into cancer cells is characterized by the acquisition of eight hallmarks. Among these criteria, the capability of the cancer cell to avoid the immune destruction has been noted. Thus, tumors develop mechanisms to become invisible to the immune system, such as the induction of immunosuppressive cells, which are able to inhibit the development of an efficient immune response. Molecules produced in the tumor microenvironment are involved in the occurrence of an immunosuppressive microenvironment. Recently, it has been shown that vascular endothelial growth factor A (VEGF-A) exhibits immunosuppressive properties in addition to its pro-angiogenic activities. VEGF-A can induce the accumulation of immature dendritic cells, myeloid-derived suppressor cells, regulatory T cells, and inhibit the migration of T lymphocytes to the tumor. Other pro-angiogenic factors such as placental growth factor (PlGF) could also participate in tumor-induced immunosuppression, but only few works have been performed on this point. Here, we review the impact of pro-angiogenic factors (especially VEGF-A) on immune cells. Anti-angiogenic molecules, which target VEGF-A/VEGFR axis, have been developed in the last decades and are commonly used to treat cancer patients. These drugs have anti-angiogenic properties but can also counteract the tumor-induced immunosuppression. Based on these immunomodulatory properties, anti-angiogenic molecules could be efficiently associated with immunotherapeutic strategies in preclinical models. These combinations are currently under investigation in cancer patients.

Single anastomosis or mini-gastric bypass: long-term results and quality of life after a 5-year follow-up.

BACKGROUND Laparoscopic mini-gastric bypass (LMGB) is an alternative to the laparoscopic Roux-en-Y gastric bypass (LRYGB), which is considered to be the gold standard in the treatment of morbid obesity. OBJECTIVES Present 5-year results of 175 patients who had undergone a LMGB between October 2006 and October 2008. SETTING University public hospital, France. METHODS Complete follow-up was available in 126 of 175 patients (72%) who had LMGB. Mortality, morbidity, weight loss, co-morbidities, and quality of life were assessed. Weight loss was determined as a change in body mass index (BMI) and percent excess BMI loss (%EBMIL). Quality of life in the treatment group was analyzed using the Gastrointestinal Quality of Life Index (GIQLI) and was compared with a retrospectively case matched preoperative control group. RESULTS There were no deaths. Thirteen patients (10.3%) developed major complications. Marginal ulcers occurred in 4% of patients. Incapacitating biliary reflux developed in 2 (1.6%) who required conversion into RYGB. Gastric pouch dilation occurred in 4 patients (3.2%) and inadequate weight loss with severe malnutrition in 2 (1.6%). At 5 years, mean BMI was 31±6 kg/m(2) and mean %EBMIL was 71.5%±26.5%. Postoperative GIQLI score of the treatment group was significantly higher than preoperative score of the control group (110.3±17.4 versus 92.5±15.9, P<.001). Social, psychological, and physical functions were increased significantly. No significant differences were found in gastroesophageal reflux or diarrhea symptoms between the 2 groups. Long-term follow-up showed an improvement in all co-morbidities. CONCLUSIONS At 5 years, LMGB was safe, effective, and provided interesting quality of life results.

Colorectal cancer and immunity: what we know and perspectives.

Strong evidence supports the concept of immunosurveillance and immunoediting in colorectal cancer. In particular, the density of T CD8⁺ and CD45⁺ lymphocyte infiltration was recently shown to have a better prognostic value than the classic tumor node metastasis classification factor. Other immune subsets, as macrophages, natural killer cells or unconventionnal lymphocytes, seem to play an important role. Induction of regulatory T cells (Tregs) or immunosuppressive molecules such as PD-1 or CTLA-4 and downregulation of antigen-presenting molecules are major escape mechanisms to antitumor immune response. The development of these mechanisms is a major obstacle to the establishment of an effective immune response, but also to the use of immunotherapy. Although immunotherapy is not yet routinely used in colorectal cancer, we now know that most treatments used (chemotherapy and biotherapy) have immunomodulatory effects, such as induction of immunogenic cell death by chemotherapy, inhibition of immunosuppression by antiangiogenic agents, and antibody-dependent cytotoxicity induced by cetuximab. Finally, many immunotherapy strategies are being developed and tested in phase I to III clinical trials. The most promising strategies are boosting the immune system with cytokines, inhibition of immunoregulatory checkpoints, vaccination with vectorized antigens, and adoptive cell therapy. Comprehension of antitumor immune response and combination of the different approaches of immunotherapy may allow the use of effective immunotherapy for treatment of colorectal cancer in the near future.

Induction of resident memory T cells enhances the efficacy of cancer vaccine

Tissue-resident memory T cells (Trm) represent a new subset of long-lived memory T cells that remain in tissue and do not recirculate. Although they are considered as early immune effectors in infectious diseases, their role in cancer immunosurveillance remains unknown. In a preclinical model of head and neck cancer, we show that intranasal vaccination with a mucosal vector, the B subunit of Shiga toxin, induces local Trm and inhibits tumour growth. As Trm do not recirculate, we demonstrate their crucial role in the efficacy of cancer vaccine with parabiosis experiments. Blockade of TFGβ decreases the induction of Trm after mucosal vaccine immunization, resulting in the lower efficacy of cancer vaccine. In order to extrapolate this role of Trm in humans, we show that the number of Trm correlates with a better overall survival in lung cancer in multivariate analysis. The induction of Trm may represent a new surrogate biomarker for the efficacy of cancer vaccine. This study also argues for the development of vaccine strategies designed to elicit them.

Signet-ring cell carcinoma of the stomach: Impact on prognosis and specific therapeutic challenge.

While the incidence of gastric cancer has decreased worldwide in recent decades, the incidence of signet-ring cell carcinoma (SRCC) is rising. SRCC has a specific epidemiology and oncogenesis and has two forms: early gastric cancer, which can be resected endoscopically in some cases and which has a better outcome than non-SRCC, and advanced gastric cancer, which is generally thought to have a worse prognosis and lower chemosensitivity than non-SRCC. However, the prognosis of SRCC and its chemosensitivity with specific regimens are still controversial as SRCC is not specifically identified in most studies and its poor prognosis may be due to its more advanced stage. It therefore remains unclear if a specific therapeutic strategy is justified, as the benefit of perioperative chemotherapy and the value of taxane-based chemotherapy are unclear. In this review we analyze recent data on the epidemiology, oncogenesis, prognosis and specific therapeutic strategies in both early and advanced SRCC of the stomach and in hereditary diffuse gastric cancer.

Open total gastrectomy with Roux-en-Y reconstruction for a chronic fistula after sleeve gastrectomy

BACKGROUND Surgery appears to be the best treatment option for a chronic fistula after laparoscopic sleeve gastrectomy (LSG). Conservative procedures (conversion into a Roux-en-Y gastric bypass, Roux-limb placement) have proven their feasibility and efficacy, but an open total gastrectomy (TG) is sometimes required in challenging situations. OBJECTIVES To assess outcomes from 12 consecutive patients who underwent surgery for a post-sleeve gastrectomy chronic fistula (PSGCF) between January 2004 and February 2012. SETTING University public hospital, France. METHODS Patients with a PSGCF who underwent surgery were included in this retrospective study. Mortality, morbidity (i.e., Clavien-Dindo score), weight loss, and nutritional status were assessed. RESULTS Twelve of 57 patients (21%) with a post-LSG leak developed a PSGCF. There were 3 men (25%). Mean age was 39±9 years and mean preoperative body mass index was 35±5 kg/m2. All 12 patients underwent an open total gastrectomy with an esojejunostomy (TG). Conservative procedures were considered but not possible. The mean follow-up period was 38±11 months. The mean delay between LSG and TG was 12±6 months. Intraoperative discovery of multiple (>2) gastric fistulas was reported in 9 patients (75%). There were no deaths, but morbidity rate was 50%. Early postoperative fistula occurred in 3 patients (anastomosis n = 1, duodenal stump n = 2). None of these patients required further surgery. The median healing time of the fistula was 37 days (range 24-53). Promising results from weight loss and nutritional status were found at the end of the follow-up. CONCLUSION A salvage open TG is a well-tolerated and reproducible salvage procedure for cases of a PSGCF, when conservative procedures are not possible.

Intraoperative Enteroscopy: Is There Still a Role?

Intraoperative enteroscopy (IOE) to explore obscure gastrointestinal bleeding is now rarely indicated. IOE allows complete small bowel exploration in 57% to 100% of cases, finds a bleeding source in 80% of cases, allows the recurrence-free management of gastrointestinal bleeding in 76% of cases, but carries a high morbidity and mortality. IOE only remains indicated to guide the intraoperative treatment of preoperatively identified small bowel lesions when nonoperative treatments are unavailable and/or when intraoperative localization by external examination is impossible.

Rôle du VEGF dans l’épuisement des lymphocytes T intratumoraux

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