MCL Cells in Tumor Microenvironment Impair T-Cell Metabolic Fitness and Effector Function

Background: Mantle cell lymphoma (MCL) is an aggressive, incurable B cell malignancy. Major advances have been achieved with the development of clinically effective targeted agents including BTK and BCL-2 inhibitors. However, patients often relapse after these treatments. The emerging immune therapies combining immune checkpoint blockade and adoptive T-cell transfer are becoming increasingly desirable, but patient responses are heterogeneous, with a significant rate of failure. Tumor microenvironment (TME) plays an important role by inducing immune checkpoint and immune suppressive signaling or creating a metabolic barrier to antitumor immunity, particularly effector T-cells. To evade immune defenses, tumor and stromal cells cooperate and tactically express inhibitory ligands, such as PD-L1, while upregulating immune checkpoint receptors on effector T-cells and CAR T cells, resulting in negative signaling that leads to T-cell exhaustion, one of the major challenges in CAR T-cell therapy. Limited nutrient accessibility and a hostile immunosuppressive TME posts a strong barrier to effective immune therapies, with T-cell immunity being mostly affected. Impaired metabolism may also inhibit the function of effector T-cells while promoting suppressive activity of regulatory T-cells. Results: Our recent transcriptomic analysis of primary MCL clinical specimens comprised of microenvironment cell populations, revealed that genes related to immune function were dysregulated, particularly the genes responsible for IFNG-mediated anti-tumor immunity. Proliferation in response to TCR stimulation is an important measurement for T-cell effector function and potency. Reduced proliferation upon T-cell activation denotes T-cell dysfunction. Indeed, T-cells isolated from MCL specimens especially CAR T non-response patients exhibit diminished cell division upon stimulation with anti-CD3/CD28 beads (25-75% less expansion). To recapitulate the interplay between T-cells and TME, MCL cells were co-cultured with the non-MCL fraction from the purification, and T-cells were then phenotypically profiled. Intriguingly, MCL-derived T-cells mostly displayed exhaustion phenotypes, indicated by decreased expression of T-cell activation markers (CD25, CD28, CD38, and CD71), but increased expression of exhaustion and senescence molecules (CTLA4, LAG3 and PD-1). Moreover, MCL-derived T cells failed to induce the expression of cytokine, such as INF-γ ( Conclusion: We presented evidence that MCL cancer cells suppress immune cell function by upregulating immunosuppressive signaling and forging a metabolic barrier to effector T-cells and immunotherapy. Targeting the MCL TME while enhancing T-cell metabolic fitness would dramatically advance current immunotherapy. Despite the success of checkpoint blockade and adoptive cell transfer therapy, complimentary approaches to overcome the metabolic barrier of immunosuppressive TME holds promise to dramatically enhance the efficacy of immunotherapies. Further, identification of the precise pathways and targets that determine T-cell metabolic fitness would facilitate developing new approaches to bolster current immunotherapy. Disclosures Wang: AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Acerta Pharma: Research Funding; Oncternal: Consultancy, Research Funding; Guidepoint Global: Consultancy; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Dava Oncology: Honoraria; Molecular Templates: Research Funding; Juno: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Lu Daopei Medical Group: Honoraria; InnoCare: Consultancy; OncLive: Honoraria; Verastem: Research Funding; VelosBio: Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Nobel Insights: Consultancy; Beijing Medical Award Foundation: Honoraria; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; MoreHealth: Consultancy; Targeted Oncology: Honoraria.