The immune system is critical in modulating cancer progression, but knowledge of immune composition, phenotype, and interactions with tumor is limited. We used multiplexed ion beam imaging by time-of-flight (MIBI-TOF) to simultaneously quantify in situ expression of 36 proteins covering identity, function, and immune regulation at sub-cellular resolution in 41 triple-negative breast cancer patients. Multi-step processing, including deep-learning-based segmentation, revealed variability in the composition of tumor-immune populations across individuals, reconciled by overall immune infiltration and enriched co-occurrence of immune subpopulations and checkpoint expression. Spatial enrichment analysis showed immune mixed and compartmentalized tumors, coinciding with expression of PD1, PD-L1, and IDO in a cell-type- and location-specific manner. Ordered immune structures along the tumor-immune border were associated with compartmentalization and linked to survival. These data demonstrate organization in the tumor-immune microenvironment that is structured in cellular composition, spatial arrangement, and regulatory-protein expression and provide a framework to apply multiplexed imaging to immune oncology.

A model of $s$ interacting species is considered with two types of dynamical variables. The fast variables are the populations of the species and slow variables the links of a directed graph that defines the catalytic interactions among them. The graph evolves via mutations of the least fit species. Starting from a sparse random graph, we find that an autocatalytic set (ACS) inevitably appears and triggers a cascade of exponentially increasing connectivity until it spans the whole graph. The connectivity subsequently saturates in a statistical steady state. The time scales for the appearance of an ACS in the graph and its growth have a power law dependence on $s$ and the catalytic probability. At the end of the growth period the network is highly non-random, being localized on an exponentially small region of graph space for large $s$.Comment: 13 pages REVTEX (including figures), 4 Postscript figure

Bacterial alginates are produced as 1-4-linked ␤-D-mannuronan, followed by epimerization of some of the mannuronic acid residues to ␣-L-guluronic acid. Here we report the isolation of four different epimerizationdefective point mutants of the periplasmic Pseudomonas fluorescens mannuronan C-5-epimerase AlgG. All mutations affected amino acids conserved among AlgG-epimerases and were clustered in a part of the enzyme also sharing some sequence similarity to a group of secreted epimerases previously reported in Azotobacter vinelandii. An algG-deletion mutant was constructed and found to produce predominantly a dimer containing a 4-deoxy-L-erythro-hex-4-enepyranosyluronate residue at the nonreducing end and a mannuronic acid residue at the reducing end. The production of this dimer is the result of the activity of an alginate lyase, AlgL, whose in vivo activity is much more limited in the presence of AlgG. A strain expressing both an epimerase-defective (point mutation) and a wild-type epimerase was constructed and shown to produce two types of alginate molecules: one class being pure mannuronan and the other having the wild-type content of guluronic acid residues. This formation of two distinct classes of polymers in a genetically pure cell line can be explained by assuming that AlgG is part of a periplasmic protein complex.

The formalism for discussing energy and charge distribution functions in the microcanonical ensemble is presented and applied to strings. This yields information of direct physical significance in string statistical mechanics. Above the Hagedorn energy density the free string gas exhibits a number of interesting features. For toroidal compactification, the distribution of the total energy among strings of various energies depends upon the number of noncompact spatial dimensions d . For d =O the energy is distributed uniformly among strings at all energy scales, while for d 2 3 a single string captures most of the energy. The imposition of conservation laws does not alter this qualitative picture. We show that the d = 1 and d = 2 cases are qualitatively different from the others.