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

Abstract: This Urgent Supplement is addressing the possible effects of cancer therapies, and PD-1 blockade inparticular, on immune responses to COVID-19 infection and vaccination. The primary objective of the parentproposal CA243486 entitled "T cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade" is todetermine the function of T cell receptors in the molecular mechanism of resistance to PD-1 checkpointblockade.The COVID-19 pandemic underscores the urgent need for effective vaccines and treatments, especially inimmunocompromised individuals including majority of cancer patients. Previously reported data on animalvaccination against coronaviruses (CoV), including SARS-CoV, demonstrated that parenteral or intramuscularimmunization, which predominantly activates systemic immunity, may be inadequate in prevention of these andother respiratory tract infections. Since respiratory mucosa is a primary target for CoV, it has beendemonstrated that targeted mucosal immunization could be a much more effective strategy as it involvesactivation of all types of adaptive immunity: systemic, mucosal and cellular. It has been shown that resistanceto SARS-CoV infection in mice is primarily driven by cellular immunity represented by the resident memory Tcells. In humans, SARS-CoV-specific memory T cells have been detected in the peripheral blood of SARSpatients 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 elicitinglong-lasting cellular immunity and (2) checkpoint blockade can elevate the T cell response during COVID-19vaccination. In this supplement to our parent grant we propose to identify SARS-CoV2 specific T cell epitopesin cancer patients and healthy individuals (Aim 1) and utilize the most immunogenic epitopes in engineering ofa recombinant vaccine library (Aim 2). Since short peptide epitopes are poor immunogens, we will utilize anon-toxic cholera toxin B (CTB) protein as a mucosal adjuvant and as a carrier for targeted delivery ofimmunogens to the lung dendritic cells (Aim 2). Next, the vaccine library will be tested for immunogenicityusing mouse models with and without PD-1 blockade to evaluate the effect of checkpoint blockade on T cellactivation during vaccination. The most efficient vaccine prototype will be further validated using a SARS-CoV2mouse model (Aim 3). This project will help to evaluate the role of T cells in immunity to COVID-19 in healthyindividuals and cancer patients, test the efficacy of a novel vaccine using in in vivo mouse model anddetermine the role of PD-1 blockade in T cell response to immunization.