부산대학교 도서관

Therapeutic benefit to immune checkpoint blockade (ICB) is currently limited to the subset of cancers thought to possess a sufficient tumor mutational burden (TMB) to allow for the spontaneous recognition of neoantigens (NeoAg) by autologous T cells. We explored whether the response to ICB of an aggressive low-TMB squamous cell tumor could be improved through combination immunotherapy using functionally defined NeoAg as targets for endogenous [CD4.sup.+] and [CD8.sup.+] T cells. We found that, whereas vaccination with [CD4.sup.+] or [CD8.sup.+] NeoAg alone did not offer prophylactic or therapeutic immunity, vaccines containing NeoAg recognized by both subsets overcame ICB resistance and led to the eradication of large established tumors that contained a subset of PD-LV tumor-initiating cancer stem cells (tCSC), provided the relevant epitopes were physically linked. Therapeutic [CD4.sup.+]/[CD8.sup.+]T cell NeoAg vaccination produced a modified tumor microenvironment (TME) with increased numbers of NeoAg-specific [CD8.sup.+] T cells existing in progenitor and intermediate exhausted states enabled by combination ICB-mediated intermolecular epitope spreading. We believe that the concepts explored herein should be exploited forthe development of more potent personalized cancer vaccines that can expand the range of tumors treatable with ICB.
Introduction Antibody-mediated blockade of PD-1 and CTLA-4 has been shown to therapeutically enhance preexisting neoantigen-specific (NeoAg-specific) [CD8.sup.+] T cell responses in several human tumors (1). Recent findings support that clinical [...]