ABSTRACT
Synergistic combinations of immunotherapeutic agents can improve the performance of anti-cancer therapies but may lead to immune-mediated adverse effects. These side-effects can be overcome by using a tumor-specific delivery system. Here, we report a method of targeted immunotherapy using an attenuated Salmonella typhimurium (SAM-FC) engineered to release dual payloads: cytolysin A (ClyA), a cytolytic anti-cancer agent, and Vibrio vulnificus flagellin B (FlaB), a potent inducer of anti-tumor innate immunity. Localized secretion of ClyA from SAM-FC induces immunogenic cancer cell death and promotes release of tumor-specific antigens and damage-associated molecular patterns, which establish long-term antitumor memory. Localized secretion of FlaB promotes phenotypic and functional remodeling of intratumoral macrophages that markedly inhibits tumor metastasis in mice bearing tumors of mouse and human origin. Both primary and metastatic tumors from bacteria-treated female mice are characterized by massive infiltration of anti-tumorigenic innate immune cells and activated tumor-specific effector/memory T cells; however, the percentage of immunosuppressive cells is low. Here, we show that SAM-FC induces functional reprogramming of the tumor immune microenvironment by activating both the innate and adaptive arms of the immune system and can be used for targeted delivery of multiple immunotherapeutic payloads for the establishment of potent and long-lasting antitumor immunity.
Subject(s)
Immunotherapy , Salmonella typhimurium , Tumor Microenvironment , Animals , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Salmonella typhimurium/immunology , Salmonella typhimurium/drug effects , Female , Mice , Humans , Immunotherapy/methods , Cell Line, Tumor , Immunity, Innate/drug effects , Mice, Inbred C57BL , Flagellin/immunology , Vibrio vulnificus/immunology , Vibrio vulnificus/drug effects , Macrophages/immunology , Macrophages/drug effects , Neoplasms/immunology , Neoplasms/therapy , Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Antineoplastic Agents/administration & dosageABSTRACT
Vietnam has been identified as a country at high-risk for emergence and re-emergence of zoonotic diseases. The government of Vietnam recognized five priority zoonoses, including highly pathogenic avian influenza, rabies, leptospirosis, anthrax, and Streptococcus suis, and established a framework for One Health investigation and response to these diseases. From July 2020 to February 2021, quantitative data of zoonoses were collected from an online survey in 61 of 63 provinces based on either clinical diagnosis or laboratory confirmation. The responses were followed up by using in-depth interviews, and scientific literatures on zoonoses in Vietnam during 2010 to 2020 were reviewed. A total of 234 human health professionals and 95 animal health professionals responded to the survey. The proportion of clinical-based respondents was higher than laboratory-based respondents in both human health (130/234, 55.6%) and animal health (65/95, 68.4%) sectors. There were differences in the reported frequency of zoonoses between human and animal health professionals, and between clinical-based and laboratory-based respondents. Rabies was the most serious zoonotic disease based on the number of human cases and the geographic distribution. No human cases of avian influenza infection have been reported since 2015, although the H5 subtype viruses have been found in poultry. Besides, some bacterial, fungal, and parasitic zoonoses were detected in both humans and animals. Out of the 75 zoonoses identified, we recommend that the original five prioritized zoonoses, plus 24 additional zoonoses, should be targeted for future prevention, detection, and control under One Health approach in Vietnam.