Adoptive cell transfer (ACT) therapies have failed to fulfill their therapeutic promise due, having employed ineffective cell populations - short-lived, exhausted, and terminally differentiated - for transfer into patients. A lack of means for developing long-lived T cell potency has hampered ACT advancement. Understanding and manipulating the mechanistic pathways that sustain T cell memory will potentially unlock durable responses to tumors. The IL-17-producing CD4+ T cell subset, Th17, has recently demonstrated long-term memory to tumors compared to Th1 cells. We first reported that robust function of Th17 cells critically requires the inducible costimulator (ICOS), a finding important considering we found the classic costimulatory molecule, CD28, to impair antitumor Th17 generation. Our studies now reveal that, in contrast to CD28, stimulating Th17 cells in vitro with ICOS endows them with a superior ability to kill established B16F10 melanoma when transferred into lymphodepleted mice. Importantly, the antitumor potency of ICOS-stimulated Th17 appears to be associated with the signal's endowing Th17 with durable memory properties;ICOS-stimulated cells persist long-term in vivo and mount rapid recall responses against B16F10 re-challenge. Further, CD28-stimulated Th17 cells, while poorly functional, could regain functionality following stimulation with certain pharmaceutical reagents (e.g., insulin, TWS119);importantly, these drugs may operate by activating cellular pathways downstream of the ICOS signal. As another route to bolstering treatment - and further demonstrating the importance of ICOS - we found that administration of an ICOS (but not CD28) agonist antibody to mice further augmented Th17 treatment outcome without the need for host preconditioning. We propose to gain insight into Th17 long-term tumor immunity and durable memory generation, hypothesizing that ICOS co-stimulation is critical for generating Th17 cells with long-lived memory responses to tumor;targeting components of the ICOS pathway may lead to durable efficacy of tumor immunotherapy.
Aim 1 will identify mechanisms by which ICOS co-stimulation maintains long-term memory and antitumor activity of Th17 cells, by studying the ICOS-induced pathways that bolster long-term cell persistence in the Braf/Pten mice with metastatic melanoma.
Aim 2 will characterize the mechanism(s) by which pharmaceutical reagents trigger ICOS pathways to rescue dysfunctional human Th17 cells. Studies on the activation of PI3K/Akt by insulin, Wnt-?- catenin by TWS119 will reveal how events downstream of ICOS signaling may reverse impaired function in in vitro and in vivo human Th17 cells stimulated with CD28.
Aim 3 will determine the mechanisms by which in vivo ICOS agonist therapy augments the antitumor activity of Th17 without the need for host lymphodepletion, shedding light on ICOS agonist impact on transferred Th17, and host CTL an Treg cells, function and memory formation. Overall, the proposed research is expected to demonstrate that manipulation of the Th17 ICOS pathway may sufficiently induce durable protection against the recurrence of advanced malignancies.

Public Health Relevance

We seek to understand the costimulatory pathways that lead to memory Th17 cells, which hold promise in the context of adoptive immunotherapy for mounting prolonged, robust responses against cancer. Our mechanistic studies of the ICOS signal's activation of T cell antitumor function, metabolism and memory phenotype will allow us to harness those pathways to generate more potent, persistent T cells and elicit prolonged positive patient immune responses against cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Yovandich, Jason L
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Medical University of South Carolina
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Majchrzak, Kinga; Nelson, Michelle H; Bailey, Stefanie R et al. (2016) Exploiting IL-17-producing CD4+ and CD8+ T cells to improve cancer immunotherapy in the clinic. Cancer Immunol Immunother 65:247-59
Nelson, Michelle H; Bowers, Jacob S; Bailey, Stefanie R et al. (2016) Toll-like receptor agonist therapy can profoundly augment the antitumor activity of adoptively transferred CD8(+) T cells without host preconditioning. J Immunother Cancer 4:6
Bowers, Jacob S; Nelson, Michelle H; Kundimi, Sreenath et al. (2015) Dendritic Cells in Irradiated Mice Trigger the Functional Plasticity and Antitumor Activity of Adoptively Transferred Tc17 Cells via IL12 Signaling. Clin Cancer Res 21:2546-57
Rubinstein, Mark P; Su, Ee Wern; Suriano, Samantha et al. (2015) Interleukin-12 enhances the function and anti-tumor activity in murine and human CD8(+) T cells. Cancer Immunol Immunother 64:539-49
Frigault, Matthew J; Lee, Jihyun; Basil, Maria Ciocca et al. (2015) Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells. Cancer Immunol Res 3:356-67
Nelson, Michelle H; Paulos, Chrystal M (2015) Novel immunotherapies for hematologic malignancies. Immunol Rev 263:90-105
Nelson, Michelle H; Diven, Marshall A; Huff, Logan W et al. (2015) Harnessing the Microbiome to Enhance Cancer Immunotherapy. J Immunol Res 2015:368736
Su, Ee W; Moore, Caitlin J; Suriano, Samantha et al. (2015) IL-2Rα mediates temporal regulation of IL-2 signaling and enhances immunotherapy. Sci Transl Med 7:311ra170
Nelson, Michelle H; Kundimi, Sreenath; Bowers, Jacob S et al. (2015) The inducible costimulator augments Tc17 cell responses to self and tumor tissue. J Immunol 194:1737-47
Chatterjee, Shilpak; Thyagarajan, Krishnamurthy; Kesarwani, Pravin et al. (2014) Reducing CD73 expression by IL1β-Programmed Th17 cells improves immunotherapeutic control of tumors. Cancer Res 74:6048-59

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