Addressing current challenges in cancer immunotherapy with mathematical and computational modeling

The goal of cancer immunotherapy is to boost a patient's immune response to a tumor. Yet, the design of an effective immunotherapy is complicated by various factors, including a potentially immunosuppressive tumor microenvironment, immune-modulating effects of conventional treatments, and therapy-related toxicities. These complexities can be incorporated into mathematical and computational models of cancer immunotherapy that can then be used to aid in rational therapy design. In this review, we survey modeling approaches under the umbrella of the major challenges facing immunotherapy development, which encompass tumor classification, optimal treatment scheduling, and combination therapy design. Although overlapping, each challenge has presented unique opportunities for modelers to make contributions using analytical and numerical analysis of model outcomes, as well as optimization algorithms. We discuss several examples of models that have grown in complexity as more biological information has become available, showcasing how model development is a dynamic process interlinked with the rapid advances in tumor-immune biology. We conclude the review with recommendations for modelers both with respect to methodology and biological direction that might help keep modelers at the forefront of cancer immunotherapy development.Comment: Accepted for publication in the Journal of the Royal Society Interfac

Simultaneous measurement of multiple parameters of a subwavelength structure based on the weak value formalism

A mathematical extension of the weak value formalism to the simultaneous measurement of multiple parameters is presented in the context of an optical focused vector beam scatterometry experiment. In this example, preselection and postselection are achieved via spatially-varying polarization control, which can be tailored to optimize the sensitivity to parameter variations. Initial experiments for the two-parameter case demonstrate that this method can be used to measure physical parameters with resolutions at least 1000 times smaller than the wavelength of illumination

Understanding How Lipopolysaccharide Impacts CD4 T Cell Immunity

Lipopolysaccharide (LPS) is a natural adjuvant synthesized by gram-negative bacteria that has profound effects on CD4 T cell responses. LPS stimulates cells through Toll-like receptor 4 (TLR4), causing the release of inflammatory cytokines and upregulation of costimulatory molecules on antigen presenting cells. The combination of signals from antigen, costimulation, and cytokines allow CD4 T cells to overcome suppressive barriers and accumulate in large numbers. T cells that are primed in an LPS-stimulated environment are programmed for long-term survival following clonal expansion. LPS is well-known for generating Th1 responses, however, under appropriate conditions it can also support differentiation into other T helper lineages, demonstrating its pleiotropic nature. Although molecular analyses have provided insights into how immune responses are controlled by LPS in vivo, its powerful adjuvant activity is also associated with toxicity. Research on partial TLR4 agonists such as monophosphoryl lipid A have demonstrated that toxicity and immunogenicity are not always linked, making them useful candidates for human vaccines. In this sense, many years of LPS research have ultimately contributed to vaccine design, and the next generation may involve studying how the balance between different CD4 T cell subsets is controlled

A mathematical model of combined CD8 T cell costimulation by 4-1BB (CD137) and OX40 (CD134) receptors.

Combined agonist stimulation of the TNFR costimulatory receptors 4-1BB (CD137) and OX40(CD134) has been shown to generate supereffector CD8 T cells that clonally expand to greater levels, survive longer, and produce a greater quantity of cytokines compared to T cells stimulated with an agonist of either costimulatory receptor individually. In order to understand the mechanisms for this effect, we have created a mathematical model for the activation of the CD8 T cell intracellular signaling network by mono- or dual-costimulation. We show that supereffector status is generated via downstream interacting pathways that are activated upon engagement of both receptors, and in silico simulations of the model are supported by published experimental results. The model can thus be used to identify critical molecular targets of T cell dual-costimulation in the context of cancer immunotherapy

Programmed cell death-1, PD-1, is dysregulated in T cells from children with new onset type 1 diabetes

Programmed death cell 1 (PD-1) is an inhibitor of T cell activation and is also functionally linked to glycolysis. We hypothesized that PD-1 expression is defective in activated T cells from children with type 1 diabetes (T1D), resulting in abnormal T cell glucose metabolism

Astrocyte Support for Oligodendrocyte Differentiation can be Conveyed via Extracellular Vesicles but Diminishes with Age.

The aging brain is associated with significant changes in physiology that alter the tissue microenvironment of the central nervous system (CNS). In the aged CNS, increased demyelination has been associated with astrocyte hypertrophy and aging has been implicated as a basis for these pathological changes. Aging tissues accumulate chronic cellular stress, which can lead to the development of a pro-inflammatory phenotype that can be associated with cellular senescence. Herein, we provide evidence that astrocytes aged in culture develop a spontaneous pro-inflammatory and senescence-like phenotype. We found that extracellular vesicles (EVs) from young astrocyte were sufficient to convey support for oligodendrocyte differentiation while this support was lost by EVs from aged astrocytes. Importantly, the negative influence of culture age on astrocytes, and their cognate EVs, could be countered by treatment with rapamycin. Comparative proteomic analysis of EVs from young and aged astrocytes revealed peptide repertoires unique to each age. Taken together, these findings provide new information on the contribution of EVs as potent mediators by which astrocytes can extert changing influence in either the disease or aged brain

Analysis of salmonid leukocytes purified by hypotonic lysis of erythrocytes

A technique that uses hypotonic lysis of erythrocytes was optimized for the purification of leukocytes from the peripheral blood and anterior kidney (pronephros) of rainbow trout Oncorhynchus mykiss. Comparisons of initial blood dilution (1:2, 1:4, and 1:6) and the time of exposure to hypotonic conditions (10, 20, and 40 s) revealed that a dilution of 1:2 provided the most complete hemolysis after 20 or 40 s in a hypotonic solution. For pronephros, a 1:5 (w:v) dilution and lysis in hypotonic solution for 10–40 s was effective in eliminating erythrocytes. Total leukocyte yield from the blood and pronephros by use of the hypotonic lysis method was comparable with that obtained by use of typical density gradient centrifugation, and cell viability was 97% or greater. Differential cell counts showed that hypotonic lysis resulted in a distribution of leukocyte cell types similar to that of density gradient separation. Hypotonic lysis of erythrocytes is a simple, rapid, and inexpensive method of purifying leukocytes from salmonid fish blood and pronephros

Intracellular immune sensing promotes inflammation via gasdermin D–driven release of a lectin alarmin

Inflammatory caspase sensing of cytosolic lipopolysaccharide (LPS) triggers pyroptosis and the concurrent release of damage-associated molecular patterns (DAMPs). Collectively, DAMPs are key determinants that shape the aftermath of inflammatory cell death. However, the identity and function of the individual DAMPs released are poorly defined. Our proteomics study revealed that cytosolic LPS sensing triggered the release of galectin-1, a β-galactoside-binding lectin. Galectin-1 release is a common feature of inflammatory cell death, including necroptosis. In vivo studies using galectin-1-deficient mice, recombinant galectin-1 and galectin-1-neutralizing antibody showed that galectin-1 promotes inflammation and plays a detrimental role in LPS-induced lethality. Mechanistically, galectin-1 inhibition of CD45 (Ptprc) underlies its unfavorable role in endotoxin shock. Finally, we found increased galectin-1 in sera from human patients with sepsis. Overall, we uncovered galectin-1 as a bona fide DAMP released as a consequence of cytosolic LPS sensing, identifying a new outcome of inflammatory cell death.Fil: Russo, Ashley J.. UConn Health School of Medicine; Estados UnidosFil: Vasudevan, Swathy O.. UConn Health School of Medicine; Estados UnidosFil: Mendez Huergo, Santiago Patricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Kumari, Puja. UConn Health School of Medicine; Estados UnidosFil: Menoret, Antoine. UConn Health School of Medicine; Estados UnidosFil: Duduskar, Shivalee. Jena University Hospital; AlemaniaFil: Wang, Chengliang. UConn Health School of Medicine; Estados UnidosFil: Pérez Sáez, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Fettis, Margaret M.. University of Florida; Estados UnidosFil: Li, Chuan. UConn Health School of Medicine; Estados UnidosFil: Liu, Renjie. University of Florida; Estados UnidosFil: Wanchoo, Arun. University of Florida; Estados UnidosFil: Chandiran, Karthik. UConn Health School of Medicine; Estados UnidosFil: Ruan, Jianbin. UConn Health School of Medicine; Estados UnidosFil: Vanaja, Sivapriya Kailasan. UConn Health School of Medicine; Estados UnidosFil: Bauer, Michael. Jena University Hospital; AlemaniaFil: Sponholz, Christoph. Jena University Hospital; AlemaniaFil: Hudalla, Gregory A.. University of Florida; Estados UnidosFil: Vella, Anthony T.. UConn Health School of Medicine; Estados UnidosFil: Zhou, Beiyan. UConn Health School of Medicine; Estados UnidosFil: Deshmukh, Sachin D.. Jena University Hospital; AlemaniaFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Rathinam, Vijay A.. UConn Health School of Medicine; Estados Unido