Function of vaccine-induced lung tissue resident memory T cells in lung metastasis and COVID-19 protection

Abstract

Vaccines have been widely used for both preventative and therapeutic purposes against various types of diseases, including infectious diseases and cancer. Besides antibody responses, effective vaccine candidates should also induce sufficient protective T cell immunity to perform the cytotoxic function for eliminating viral-infected or tumor cells. In clinical research, functional T cell responses have been associated with better clinical outcomes in many infectious diseases and cancer. Therefore, this study aims to discover an effective vaccine strategy to provide protection in different disease models and to investigate the underlying mechanism. I hypothesize that the systemic prime-mucosal boost vaccine strategy could establish protective T cell immunity against viral infection and tumor progression.

The outbreak of coronavirus disease 2019 (COVID-19) has led to the rapid development of multiple COVID-19 vaccine candidates to reduce the severe disease rate and to establish herd immunity. Although most of the vaccine regimens have shown efficacy in reducing SARS-CoV-2 lung infection in animal models and humans, insufficient attention has been given to enhancing mucosal immunity in the upper respiratory mucosa to block viral infection in nasal turbinate and potentially preventing viral transmission in human populations. To address this issue, a vaccine regimen was developed utilizing a PD1-based DNA vaccine (DNA-PD1-RBD) prime and a live attenuated influenza viral (LAIV) vaccine (LAIV-CA04-RBD and/or LAIV-HK68-RBD) boost. The results showed that the DNA-PD1-RBD i.m./EP prime plus LAIV-HK68-RBD i.n. boost vaccine regimen elicited the highest frequencies of both systemic and mucosal RBD-specific T cell responses and prevented mice from SARS-CoV-2 nasal infection in mouse models. Critically, this DNA/LAIV vaccine regimen uniquely elicited the highest frequency of RBD-specific CD8+ tissue-resident memory T cells (TRM) in the lungs of mice as compared with all vaccines tested alone including commercial vaccines. These findings provide scientific evidence that the induction of TRM in mucosal tissues may play a central role in preventing SARS-CoV-2 nasal transmission, which have significant implications to vaccine optimization for prolonged protection against COVID-19.

To further investigate the role of lung TRM against other human deadly diseases, we tested our DNA/LAIV vaccine regimen in cancer models. Lung metastasis is a common challenge in melanoma and mesothelioma patients. T cell responses, particularly higher frequencies of lung CD8+ TRM, have been shown to predict better survival rates and prognosis. However, methods and underlying mechanism to elicit a large number of CD8+ TRM cells against lung cancer remain elusive. In this study, I discovered that the DNA/LAIV vaccine regimen effectively protected mice from mesothelioma and melanoma lung metastasis by eliciting a large number of antigen-specific polyfunctional CD8+ TRM cells in lungs. The protective role of these CD8+ TRM cells was confirmed by parabiosis models. Importantly, I found that central memory T cell (TCM) generated in systemic prime immunization is the major precursor of lung TRM induced by intranasal booster immunization, thereby revealing a key mechanism of lung CD8+ TRM induction in prime-boost immunization. These findings are essential to optimize the prime-boost vaccine strategy to promote the induction of mucosal T-cell immunity for protection.