Immune evasion and altered metabolism, where glucose utilization is diverted to increased lactic acid production, are two fundamental hallmarks of cancer. Although lactic acid has long been considered a waste product of this alteration, it is now well accepted that increased lactic acid production and the resultant acidification of the tumor microenvironment (TME) promotes multiple critical oncogenic processes including angiogenesis, tissue invasion/metastasis, and drug resistance. We and others have hypothesized that excess lactic acid in the TME is responsible for suppressing anticancer immunity. Recent studies support this hypothesis and provide mechanistic evidence explaining how lactic acid and the acidic TME impede immune cell functions. In this review, we consider lactic acid’s role as a critical immunoregulatory molecule involved in suppressing immune effector cell proliferation and inducing immune cell de-differentiation. This results in the inhibition of antitumor immune responses and the activation of potent, negative regulators of innate and adaptive immune cells. We also consider the role of an acidic TME in suppressing anticancer immunity. Finally, we provide insights to help translate this new knowledge into impactful anticancer immune therapies.

Graphical Abstract Highlights d The crystal structure of HMBPP-bound intracellular BTN3A1 was determined at 1.97 Å d HMBPP forms hydrogen bonds with H 351 for efficient Vg9Vd2 T cell activation d An asymmetric intracellular dimer is involved in HMBPPmediated gd T cell activation d HMBPP doubles the binding force between extracellular BTN3A and Vg9Vd2 TCR SUMMARYHuman Vg9Vd2 T cells respond to microbial infections and malignancy by sensing diphosphate-containing metabolites called phosphoantigens, which bind to the intracellular domain of butyrophilin 3A1, triggering extracellular interactions with the Vg9Vd2 T cell receptor (TCR). Here, we examined the molecular basis of this ''inside-out'' triggering mechanism. Crystal structures of intracellular butyrophilin 3A proteins alone or in complex with the potent microbial phosphoantigen HMBPP or a synthetic analog revealed key features of phosphoantigens and butyrophilins required for gd T cell activation. Analyses with chemical probes and molecular dynamic simulations demonstrated that dimerized intracellular proteins cooperate in sensing HMBPP to enhance the efficiency of gd T cell activation. HMBPP binding to butyrophilin doubled the binding force between a gd T cell and a target cell during ''outside'' signaling, as measured by single-cell force microscopy. Our findings provide insight into the ''inside-out'' triggering of Vg9Vd2 T cell activation by phosphoantigen-bound butyrophilin, facilitating immunotherapeutic drug design.

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As a component of the innate immune cell population, γδ T cells are involved in tumor immunosurveillance and host defense against viral invasion. In this study, we demonstrated a novel function of human γδ T cells as regulatory cells by detecting their suppressive effect on the proliferation of autologous naive CD4+ T cells. These regulatory γδ T cells (γδ Tregs) could be generated in vitro by stimulating with anti-TCRγδ in the presence of TGF-β and IL-2. Similar to CD4+Foxp3+ Tregs, γδ Tregs also expressed Foxp3. Additionally, they primarily belonged to the Vδ1 subset with a CD27+CD25high phenotype. Furthermore, these γδ Tregs showed an immunoregulatory activity mainly through cell-to-cell contact. Importantly, this γδ regulatory population decreased in the peripheral blood of systemic lupus erythematosus patients, suggesting a potential mechanism in understanding the pathogenesis of systemic lupus erythematosus.

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Cell-based immunotherapy for lymphoid malignancies has gained increasing attention as patients develop resistance to conventional treatments. cd T cells, which have major histocompatibility complex (MHC)-unrestricted lytic activity, have become a promising candidate population for adoptive cell transfer therapy. We previously established a stable condition for expanding cd T cells by using anti-cd T-cell receptor (TCR) antibody. In this study, we found that adoptive transfer of the expanded cd T cells to Daudi lymphoma-bearing nude mice significantly prolonged the survival time of the mice and improved their living status. We further investigated the characteristics of these antibody-expanded cd T cells compared to the more commonly used phosphoantigen-expanded cd T cells and evaluated the feasibility of employing them in the treatment of lymphoid malignancies. Slow but sustained proliferation of human peripheral blood cd T cells was observed upon stimulation with anti-cd TCR antibody. Compared to phosphoantigen-stimulated cd T cells, the antibody-expanded cells manifested similar functional phenotypes and cytotoxic activity towards lymphoma cell lines. It is noteworthy that the anti-cd TCR antibody could expand both the Vd1 and Vd2 subsets of cd T cells. The in vitro-expanded Vd1 T cells displayed comparable tumour cell-killing activity to Vd2 T cells. Importantly, owing to higher C-C chemokine receptor 4 (CCR4) and CCR8 expression, the Vd1 T cells were more prone to infiltrate CCL17-or CCL22-expressing lymphomas than the Vd2 T cells. Characterizing the peripheral blood cd T cells from lymphoma patients further confirmed that the anti-cd TCR antibody-expanded cd T cells could be a more efficacious choice for the treatment of lymphoid malignancies than phosphoantigen-expanded cd T cells.

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