A subset of cytotoxic effector memory T cells enhances CAR T cell efficacy in a model of pancreatic ductal adenocarcinoma

Abstract

In humans, the natural killer (NK) cell marker CD161 identifies several subsets of T cells, including a polyclonal CD8 αβ T cell receptor–expressing subset with characteristic specificity for tissue-localized viruses. This subset also displays enhanced cytotoxic and memory phenotypes. Here, we characterized this unique T cell subset and determined its potential suitability for use in chimeric antigen receptor (CAR) T cell therapy. In mice, gene expression profiling among the CD161-equivalent CD8+ T cell populations (CD8+NK1.1+) revealed substantial up-regulation of granzymes, perforin, killer lectin-like receptors, and innate signaling molecules in comparison to CD8+NK1.1− T cells. Adoptive transfer of CD8+NK1.1+ cells from previously exposed animals offered substantially enhanced protection and improved survival against melanoma tumors and influenza infection compared to CD8+NK1.1− cells. Freshly isolated human CD8+CD61+ T cells exhibited heightened allogeneic killing activity in comparison to CD8+CD61− T cells or total peripheral blood mononuclear cells (PBMCs). To determine whether this subset might improve the antitumor efficacy of CAR T cell therapy against solid tumors, we compared bulk PBMCs, CD8+CD161−, and CD8+CD161+ T cells transduced with a human epidermal growth factor receptor-2 (HER2)–specific CAR construct. In vitro, CD8+CD161+ CAR-transduced T cells killed HER2+ targets faster and with greater efficiency. Similarly, these cells mediated enhanced in vivo antitumor efficacy in xenograft models of HER2+ pancreatic ductal adenocarcinoma, exhibiting elevated expression of granzymes and reduced expression of exhaustion markers. These data suggest that this T cell subset presents an opportunity to improve CAR T cell therapy for the treatment of solid tumors.

Universal allogeneic CAR T cells engineered with Sleeping Beauty transposons and CRISPR-CAS9 for cancer immunotherapy

“…73 The prevailing memory phenotype and absence of a typical T cell exhaustion profile correlated with the antitumor effects and sustained and complete tumor remission in the xenograft model. 60,74,75 Reduction of TCR alloreactivity in CAR/TCR KO T cells observed in our study exhibited its therapeutic potentials to minimize the risk of GvHD in mice, which was demonstrated in previous studies. 22,60 To our knowledge, this study is the first to demonstrate that the combination of SB transposons and CRISPR-Cas9 enables efficient manufacturing of allogeneic TCR-disrupted CD19-CAR T cells, underscoring its novelty.…”

Pooled screening of CAR T cells identifies diverse immune signaling domains for next-generation immunotherapies

“…In addition to the increased expression of MHC genes and integrins, the Cytotoxic and Memory clusters also transcribed several receptors more typical of NK cells, including KLRB1 , which encodes CD161. CD161 is expressed by a subset of T cells with characteristic tissue homing( 61 ) and increased cytotoxicity ( 62 ), and recent work has shown that CD8+CD161+ T cells define a potent effector memory subset with enhanced CAR T cell efficacy ( 63 ). To explore this further, we turned to a recent study which identified a continuous gene expression gradient of lymphocyte innateness from T cells to NK cells( 64 ).…”

Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor (CAR) for tumor immunotherapy; recent progress

“…It was speculated that switchable HER2-redirected CAR T cells are as effective as conventional HER2-redirected CAR T cells in vivo [ 121 ]. Another report has shown that HER2-specific CD8+CD161+ CAR T cells could eradicate HER2-expressing PDAC cells faster and with greater efficiency than HER2-specific CD8+CD161− CAR T cells [ 122 ]. Further, CD8+CD161+ CAR T cells could stimulate in vivo antitumor efficacy in xenograft models of HER2-expressing PDCA cells, with raised expression of granzymes and abridged expression of exhaustion markers [ 122 ].…”

“…Another report has shown that HER2-specific CD8+CD161+ CAR T cells could eradicate HER2-expressing PDAC cells faster and with greater efficiency than HER2-specific CD8+CD161− CAR T cells [ 122 ]. Further, CD8+CD161+ CAR T cells could stimulate in vivo antitumor efficacy in xenograft models of HER2-expressing PDCA cells, with raised expression of granzymes and abridged expression of exhaustion markers [ 122 ]. Besides, Thakur et al [ 123 ] employed anti-CD19 CART armed with anti-CD3 (OKT3) × anti-HER2 bispecific antibodies (HER2Bi) or anti-CD3 (OKT3) × anti-EGFR bispecific antibodies (EGFRBi) to address the cytotoxicity against HER2 or EGFR positive cancer cell lines.…”