T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade

点击翻译按钮获取中文摘要

Abstract This Urgent Supplement is addressing the possible effects of cancer therapies, and PD-1 blockade in particular, on immune responses to COVID-19 infection and vaccination. The primary objective of the parent proposal CA243486 entitled “T cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade” is to determine the function of T cell receptors in the molecular mechanism of resistance to PD-1 checkpoint blockade. The COVID-19 pandemic underscores the urgent need for effective vaccines and treatments, especially in immunocompromised individuals including majority of cancer patients. Previously reported data on animal vaccination against coronaviruses (CoV), including SARS-CoV, demonstrated that parenteral or intramuscular immunization, which predominantly activates systemic immunity, may be inadequate in prevention of these and other respiratory tract infections. Since respiratory mucosa is a primary target for CoV, it has been demonstrated that targeted mucosal immunization could be a much more effective strategy as it involves activation of all types of adaptive immunity: systemic, mucosal and cellular. It has been shown that resistance to SARS-CoV infection in mice is primarily driven by cellular immunity represented by the resident memory T cells. In humans, SARS-CoV-specific memory T cells have been detected in the peripheral blood of SARS patients six or more years post-infection despite the lack of virus-specific memory B cells. We hypothesize that (1) the long-term protection against CoV including SARS-CoV2 can be achieved by a mucosal vaccine eliciting long-lasting cellular immunity and (2) checkpoint blockade can elevate the T cell response during COVID-19 vaccination. In this supplement to our parent grant we propose to identify SARS-CoV2 specific T cell epitopes in cancer patients and healthy individuals (Aim 1) and utilize the most immunogenic epitopes in engineering of a recombinant vaccine library (Aim 2). Since short peptide epitopes are poor immunogens, we will utilize a non-toxic cholera toxin B (CTB) protein as a mucosal adjuvant and as a carrier for targeted delivery of immunogens to the lung dendritic cells (Aim 2). Next, the vaccine library will be tested for immunogenicity using mouse models with and without PD-1 blockade to evaluate the effect of checkpoint blockade on T cell activation during vaccination. The most efficient vaccine prototype will be further validated using a SARS-CoV2 mouse model (Aim 3). This project will help to evaluate the role of T cells in immunity to COVID-19 in healthy individuals and cancer patients, test the efficacy of a novel vaccine using in in vivo mouse model and determine the role of PD-1 blockade in T cell response to immunization.