Examining IL-15 and IL-7 as an immunotherapy agent in cancer and AIDS

Division Of Basic Sciences - Nci

Investigators

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Abstract

Understanding of the cellular mechanisms controlling expression shed new light in the biology and regulation of IL-15, led to the identification of the bioactive heterodimeric form of IL-15 and provided methods for the efficient production and clinical application of this cytokine (Bergamaschi, J. Biol. Chem. 283: 4189, 2008; Bergamaschi, Blood 120: e1-8, 2012; Bergamaschi, Cancers 13, 2021). We have shown that hetIL-15 greatly increases lymphocyte infiltration in several tumors in mouse models and in macaques, suggesting a general method to increase lymphocyte infiltration, which is associated with anti-tumor activity. We have performed first-in-human clinical trials of hetIL-15 in metastatic cancers (Conlon, JITC:e003388. 2021) and also in combination with anti-PD-1 check point inhibitor (NCT02452268; collaboration with Novartis). hetIL-15 is extensively studied in mouse tumor models where we demonstrated the rapid interaction of lymphoid and myeloid cell networks resulting in changes in numbers and migration of different cell populations. Extensive transcriptomics and proteomics analysis has revealed additional pathways affected by hetIL-15 (Bergamaschi, J. Immunother. Cancer: 8:e000599, 2020; Bergamaschi, Cancers 13, 2021). We have studied the effects of hetIL-15 in the number and properties of Dendritic Cells (DC) in tumors. DC participate in a network of cells that are induced during hetIL-15 treatment and in turn support more recruitment of effector cells in tumor sites. We showed that locoregional monotherapy with hetIL-15 in a triple-negative breast cancer (TNBC) orthotopic mouse model resulted in tumor eradication in 40% of treated mice, reduction of metastasis and induction of immunological memory against breast cancer cells (Stellas, Cell Reports, 42:112501, 2023). hetIL-15 reshaped the tumor microenvironment by promoting the intratumoral accumulation of cytotoxic lymphocytes, conventional type 1 dendritic cells (cDC1s) and a DC population expressing both CD103 and CD11b markers. These CD103intCD11b+DCs share phenotypic and gene expression characteristics with both cDC1s and cDC2s, have transcriptomic profiles more similar to monocyte derived DCs (moDCs) and correlate with tumor regression. Therefore, hetIL-15, a cytokine directly affecting lymphocytes and inducing cytotoxic cells, has also an indirect rapid and significant effect on the recruitment of myeloid cells, initiating a cascade for tumor elimination through innate and adoptive immune mechanisms. The intratumoral CD103intCD11b+DC population induced by hetIL-15 may be the target for the development of additional cancer immunotherapy approaches. Together, our studies in mouse orthotopic models showed that DC populations correlate with tumor regression and reveal additional beneficial effects of hetIL-15 in inducing or enhancing long term protective immune response against tumors. In addition to cancer immunotherapy, IL-15 has generated strong interest for clinical use to treat HIV infection, especially in protocols targeting viral eradication or a functional cure. The use of IL-15 as an immune therapeutic agent against HIV infection is based on its effects as a growth factor and key regulator of cytotoxic responses mediated by both the innate (NK cells) and the adaptive (CTL) arms of the immune system. Importantly, hetIL-15 treatment promotes the entrance of cytotoxic (GrzB+) CD8+ T cells in the B cell follicles, areas within the LN where CTL are typically excluded and where SIV/HIV infected follicular helper CD4+ T cells reside. hetIL-15 treatment led to significant decrease in cell-associated viral RNA within the LN as well as in plasma viremia in SHIV infected macaques (Watson, PLoS Pathog. 14: e1006902, 2018). In a collaborative effort, we further reported that a IL-15 transcriptional signature response to a viral RhCMV/SIV vaccine strongly correlated with protection (Barrenas, PLoS Pathog 17:e1009278; 2021). We have expanded this concept and are testing the contribution of a combinatorial treatment including hetIL-15 in reducing reservoir in the SIV infected ART-treated macaques. We found that a combinatorial treatment including anti-PD-1 and NAb led to reduction of the viral reservoir. Detailed underlying mechanisms are being investigated and treatment regimens are being improved in on-going study. These pre-clinical data demonstrate that harnessing the immune system using different immunological interventions during ART-treatment can play a critical role the reduction of the reservoir and the control of viremia. We continue to work on optimizing this proof-of-concept study. IL-7 is another homeostatic cytokine like IL-15, belonging to the gamma-chain family. Like for IL-15, we employed a dose-escalation regimen in rhesus macaques to deliver human-cell produced glycosylated IL-7, a cytokine critical for development and maintenance of T lymphocytes (Pandit, iScience 26: 105929, 2023). We showed that IL-7 increased proliferation and survival of T cells and triggered several chemokines and cytokines. Induction of CXCL13 in lymph nodes (LN) led to a remarkable increase of B cells in LN, proliferation of germinal center follicular T helper cells and elevated IL-21 levels indicting an increase in follicle activity. Transcriptomics analysis showed induction of IRF-7 and Flt3L, which was linked to increased frequency of circulating plasmacytoid dendritic cells (pDC) on IL-7 treatment. These pDC expressed higher levels of CCR7, homed to LNs, and were associated with upregulation of type-1 interferon gene signature and increased production of IFN-a2a on TLR stimulation. Superior effects and dose-sparing advantage was observed by the step-dose regimen. Taken together, our results indicate that IL-7 therapy acts at different levels in the immune system involving both lymphoid and myeloid compartments. T cell immunity could be strengthened by promoting redistribution, survival, and proliferation of T cells, whereas the influx of B cells and Tfh activation can result in improved humoral immune responses. The role of IL-7 at the interface of cell and humoral adaptive immunity can be exploited in vaccine strategies and in immunotherapeutic regimen. Because IL-7 functions at the apex of lymphopoiesis in the bone marrow and is crucial for lymph node development, our findings demonstrate the importance of delineating the systemic effects of IL-7 beyond its direct targets, which is part of on-going work. Together, IL-7 treatment promoted proliferation of T cells and increase of B lymphocytes in LN together with activated Tfh cells and pDC producing type-1 interferon, an immune landscape that is the potential to enhance cellular and humoral adaptive immune responses.