Th17 cells are refractory to senescence and retain robust antitumor activity after long-term ex vivo expansion

Abstract

Adoptive immunotherapy for solid tumors relies on infusing large numbers of T cells to mediate successful antitumor responses in patients. While long-term rapid-expansion protocols (REPs) produce sufficient numbers of CD8 T cells for treatment, they also cause decline in the cell's therapeutic fitness. In contrast, we discovered that IL-17-producing CD4 T cells (Th17 cells) do not require REPs to expand 5,000-fold over 3 weeks. Also, unlike Th1 cells, Th17 cells do not exhibit hallmarks of senescence or apoptosis, retaining robust antitumor efficacy in vivo. Three-week-expanded Th17 cells eliminated melanoma as effectively as Th17 cells expanded for 1 week when infused in equal numbers into mice. However, treating mice with large recalcitrant tumors required the infusion of all cells generated after 2 or 3 weeks of expansion, while the cell yield obtained after 1-week expansion was insufficient. Long-term-expanded Th17 cells also protected mice from tumor rechallenge including lung metastasis. Importantly, 2-week-expanded human chimeric antigen receptor-positive (CAR) Th17 cells also retained their ability to regress human mesothelioma, while CAR Th1 cells did not. Our results indicate that tumor-reactive Th17 cells are an effective cell therapy for cancer, remaining uncompromised when expanded for a long duration owing to their resistance to senescence.

Decreased RORC expression and downstream signaling in HTLV‐1‐associated adult T‐cell lymphoma/leukemia uncovers an antiproliferative IL17 link: A potential target for immunotherapy?

“…41,43 Of interest, two recent papers have demonstrated a role for IL-10 as an unexpected proliferative trigger of infected CD4+ T-cell clones and, possibly, leukemogenesis. 44,45 Corroborating these findings, IL10 was found to be a significant (r = 0.36, p = 0.013) member of the proliferative gene module, together with PCNA and MKI67, in our WGCNA analysis. In addition, RNAseq analysis of purified cells with a CD4 + CCR4 + CD26-CD7-leukemic phenotype from an independent UK cohort revealed IL17C is expressed in "ATL-like" cells.…”

“…Defects in the Th17 axis increase vulnerability to S. aureus and Candida albicans infections, whereas in vivo S. aureus primed memory Th17 cells inhibited IL‐17 production and increased IL‐10 production . Of interest, two recent papers have demonstrated a role for IL‐10 as an unexpected proliferative trigger of infected CD4+ T‐cell clones and, possibly, leukemogenesis . Corroborating these findings, IL10 was found to be a significant ( r = 0.36, p = 0.013) member of the proliferative gene module, together with PCNA and MKI67 , in our WGCNA analysis.…”

Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy

“…This situation can be further exacerbated by conventional ex vivo cell manufacturing processes (19,20,57,58). We therefore next asked whether AKTi preserves key markers of cellular differentiation and effector function relative to an unstimulated starting population of T cells.…”

“…Thus, relatively differentiated T cell products are generated using many current clinical manufacturing methods for genetically engineered T cells because these methods focus primarily on the generation of large numbers of antitumor cells (19,20). This is especially true in heavily pretreated patients who have starting apheresis populations containing a paucity of naive/ early memory T cells (21)(22)(23).…”

Harnessing neoantigen specific CD4 T cells for cancer immunotherapy

“…Lastly, many studies have indicated that a T H 1 phenotype is preferable for ACT; however, recent work indicates that T H 17 polarized CD4 + T cells are able to exert superior antitumor immunity over T H 1 cells by resisting apoptosis and senescence 106 . Importantly, tumor destruction still depends on the T H 1 cytokine IFNγ and CD8 + T cells.…”