Intratumoral expression of IL-12 from lentiviral or RNA vectors acts synergistically with TLR4 agonist (GLA) to generate anti-tumor immunological memory

Systemic interleukin-12 (IL12) anti-tumor therapy is highly potent but has had limited utility in the clinic due to severe toxicity. Here, we present two IL12-expressing vector platforms, both of which can overcome the deficiencies of previous systemic IL12 therapies: 1) an integrating lentiviral vector, and 2) a self-replicating messenger RNA formulated with polyethyleneimine. Intratumoral administration of either IL12 vector platform resulted in recruitment of immune cells, including effector T cells and dendritic cells, and the complete remission of established tumors in multiple murine models. Furthermore, concurrent intratumoral administration of the synthetic TLR4 agonist glucopyranosyl lipid A formulated in a stable emulsion (GLA-SE) induced systemic memory T cell responses that mediated complete protection against tumor rechallenge in all survivor mice (8/8 rechallenged mice), whereas only 2/6 total rechallenged mice treated with intratrumoral IL12 monotherapy rejected the rechallenge. Taken together, expression of vectorized IL12 in combination with a TLR4 agonist represents a varied approach to broaden the applicability of intratumoral immune therapies of solid tumors.

The Immune Response to Respiratory Viruses: From Start to Memory

Biomedical research has long strived to improve our understanding of the immune response to respiratory viral infections, an effort that has become all the more important as we live through the consequences of a pandemic. The disease course of these infections is shaped in large part by the actions of various cells of the innate and adaptive immune systems. While these cells are crucial in clearing viral pathogens and establishing long-term immunity, their effector mechanisms may also escalate into excessive, tissue-destructive inflammation detrimental to the host. In this review, we describe the breadth of the immune response to infection with respiratory viruses such as influenza and respiratory syncytial virus. Throughout, we focus on the host rather than the pathogen and try to describe shared patterns in the host response to different viruses. We start with the local cells of the airways, onto the recruitment and activation of innate and adaptive immune cells, followed by the establishment of local and systemic memory cells key in protection against reinfection. We end by exploring how respiratory viral infections can predispose to bacterial superinfection.

Systemic CD8 T-Cell Memory Response to a Salmonella Pathogenicity Island 2 Effector Is Restricted to Salmonella enterica Encountered in the Gastrointestinal Mucosa

ABSTRACT To better understand the evolution of a systemic memory response to a mucosal pathogen, we monitored antigen-specific OT1 CD8 T-cell responses to a fusion of the SspH2 protein and the peptide SIINFEKL stably expressed from the chromosome of Salmonella enterica and loaded into the class I pathway of antigen presentation of professional phagocytes through the Salmonella pathogenicity island 2 type III secretion system (TTSS). This strategy has revealed that effector memory CD8 T cells with low levels of CD62L expression (CD62Llow) are maintained in systemic sites months after vaccination in response to low-grade infections with Salmonella. However, the CD8 T-cell pool eventually declines. Low numbers of central memory cells surviving after prolonged resting from an antigen encounter can nevertheless reconstitute the systemic effector memory pool in a route-specific recall response to cognate antigens encountered in the gut. Accordingly, populations of CD62Lhigh interleukin-7 receptor-positive progenitor central memory cells grafted into naïve mice expand in response to orally administered Salmonella expressing the chromosomal translational fusion of sspH2 and the sequence encoding the SIINFEKL peptide but fail to proliferate following systemic stimulation. Moreover, populations of systemic memory CD8 T cells restricted to Salmonella in oral vaccines selectively expand in response to cognate antigens presented by cells isolated from mesenteric lymph nodes (MLN). Together, these findings have revealed the imprinting of systemic CD8 central memory T-cell recall responses against enteropathogens by MLN. MLN restriction represents a novel mechanism by which systemic CD8 T-cell immunity is confined to periods of high risk for extraintestinal dissemination.