Biology subjects

Luddy, K.

Publications and source records attributed to Luddy, K..

5 recordsLinked to original sources

bioRxiv2019

Lymph Nodes Inhibit T-cell Effector Functions Locally by Establishing Acidic Niches

Lymph nodes are an essential component of the adaptive immune response where antigen-presenting cells are closely housed with their cognate effector cells. Protection of lymph node resident cells from activated immune cells in such close quarters would need to be robust and reversible. Effector functions of T-cells are profoundly and reversibly inhibited by an acidic microenvironment. The underlying mechanisms of this inhibition are unknown, but may relate to glycolysis, which is obligatory for expression of effector functions. Here, we demonstrate that acidification rapidly and potently inhibits monocarboxylate transporter-dependent lactic acid efflux, which dually inhibits glycolysis by end-product accumulation and by reducing cytoplasmic pH. Based on the robustness of these responses, we propose that acid-evoked T-cell inhibition is physiologically important, and that lymph nodes are a natural site for such modulation. Using multiple imaging techniques, we show that paracortical T-zones of lymph nodes are highly acidic. We further show that T-cells can be activated by dendritic cells at low pH, and their effector functions are restored rapidly upon increasing pH. Thus, we describe a novel physiological mechanism whereby activated T-cells are kept in stasis by acidosis whilst resident in lymph nodes.

physiology↗

bioRxiv2019

Intermittent hormonal therapy shows similar outcome than SOC in ER+ breast cancer preclinical model.

Clinical breast cancers in which at least 10% of cells express the estrogen receptor are labeled as \"ER positive.\" First line therapy for these patients is typically continuous administration of anti-estrogen drugs at maximum tolerated dose (MTD) until progression. In the vast majority of patients, resistance to hormone therapy evolves in the breast cancer cells within 2 years leading to treatment failure and tumor progression. In prior studies, we have demonstrated continuous application of MTD chemotherapy results in evolutionary dynamics (termed \"competitive release\") that accelerates proliferation of treatment-resistance populations. In contrast, evolution-informed application of treatment reduces drug administration to maintain substantial populations of therapy-sensitive cells to reduce proliferation of resistant phenotypes. Prior pre-clinical and clinical studies have shown this strategy can delay or prevent proliferation of resistant cells and prolong time to progression (TTP). We hypothesize that similar dynamics may be observed in hormonal therapy of ER+ breast cancers. Here we address two important dynamics. First, we consider a clinical scenario in which symptoms are sufficiently severe or life-threatening to require rapid and substantial tumor reduction. Can this be achieved while retaining evolutionary dynamics to subsequently delay proliferation of resistance? A second, related question is defining the cost of resistance to anti-estrogen therapy. Here, we investigated the evolutionary dynamics of resistance to anti-estrogen therapy using ER+ MCF-7 orthotropic xenografts treated with both continuous Tamoxifen as well as cycles in which estrogen stimulation is combined with estrogen suppression. As expected, continuous administration of anti-estrogen drugs successfully suppressed tumor growth. However we found that brief interruptions in drug administration permitted equal tumor control while administering up to 50% less drug and maintaining cell phenotypes that retained high levels of ER expression and lower levels of MDR1 expression. In follow-on experiments combining hormonal and chemo-therapies; we obtained similar tumor control to hormonal therapy alone but with more necrosis and significantly lower ER expression in the surviving population.

cancer biology↗

bioRxiv2018

Acidity promotes tumor progression by altering macrophage phenotype in prostate cancer

Tumors rapidly ferment glucose to lactic acid even in the presence of oxygen, and coupling high glycolysis with poor perfusion leads to extracellular acidification. Here we demonstrate that acidity, independent from lactate, augments the pro-tumor phenotype of macrophages. We used zwitterionic buffers to show that activating macrophages at pH 6.8 in vitro enhanced an IL-4-driven phenotype as measured by gene expression, cytokine profiling, and functional assays. These results were recapitulated in vivo wherein neutralizing intratumoral acidity reduced the pro-tumor phenotype of macrophages, while also decreasing tumor incidence and invasion in the TRAMP model of prostate cancer. These results were recapitulated using an in silico mathematical model that simulate macrophage responses to environmental signals. By turning off acid-induced cellular responses, our in silico mathematical modeling shows that acid-resistant macrophages can limit tumor progression. In summary, this study suggests that tumor acidity contributes to prostate carcinogenesis by altering the state of macrophage activation.

immunology↗

bioRxiv2018

Evolutionary exploitation of PD-L1 expression in hormone receptor positive breast cancer

Based on clinical data from hormone positive breast cancer patients, we determined that there is a potential tradeoff between reducing tumor burden and altering metastatic potential when administering combination therapy of aromatase inhibitors and immune checkpoint inhibitors. While hormone-deprivation therapies serve to reduce tumor size in the neoadjuvant setting pre-surgery, they may induce tumors to change expression patterns towards a metastatic phenotype. We used mathematical modeling to explore how the timing of the therapies affects tumor burden and metastatic potential with an eye toward developing a dynamic prognostic score and reducing both tumor size and risk of metastasis.

cancer biology↗

bioRxiv2018

The immune checkpoint kick start: Optimization of neoadjuvant combination therapy using game theory

An upcoming clinical trial at the Moffitt Cancer Center for women with stage 2/3 ER+breast cancer combines an aromatase inhibitor and a PD-L1 checkpoint inhibitor, and aims to lower a preoperative endocrine prognostic index (PEPI) that correlates with relapse-free survival. PEPI is fundamentally a static index, measured at the end of neoadjuvant therapy before surgery. We develop a mathematical model of the essential components of the PEPI score in order to identify successful combination therapy regimens that minimize both tumor burden and metastatic potential, based on time-dependent trade-offs in the system. We consider two molecular traits, CCR7 and PD-L1 which correlate with treatment response and increased metastatic risk. We use a matrix game model with the four phenotypic strategies to examine the frequency-dependent interactions of cancer cells. This game was embedded into an ecological model of tumor population growth dynamics. The resulting model predicts both evolutionary and ecological dynamics that track with changes in the PEPI score. We consider various treatment regimens based on combinations of the two therapies with drug holidays. By considering the trade off between tumor burden and metastatic potential, the optimal therapy plan was found to be a 1 month kick start of the immune checkpoint inhibitor followed by five months of continuous combination therapy. Relative to a protocol with both therapeutics given together from the start, this delayed regimen results in transient sub-optimal tumor regression while maintaining a phenotypic constitution that is more amenable to fast tumor regression for the final five months of therapy. The mathematical model provides a useful abstraction of clinical intuition, enabling hypothesis generation and testing of clinical assumptions.

cancer biology↗