Synergistic effects of host B7-H4 deficiency and gemcitabine treatment on tumor regression and anti-tumor T cell immunity in a mouse model.

B7-H4 (B7x/B7S1), a B7 family inhibitor of T cell activity, is expressed in multiple human cancers and correlates with decreased infiltrating lymphocytes and poor prognosis. In murine models, tumor-expressed B7-H4 enhances tumor growth and reduces T cell immunity, and blockade of tumor-B7-H4 rescues T cell activity and lowers tumor burden. This implicates B7-H4 as a target for cancer immunotherapy, yet limits the efficacy of B7-H4 blockade exclusively to patients with B7-H4+ tumors. Given the expression of B7-H4 on host immune cells, we have previously shown that BALB/c mice lacking host B7-H4 have enhanced anti-tumor profiles, yet similar 4T1 tumor growth relative to control. Given that T cell-mediated immunotherapies work best for tumors presenting tumor-associated neoantigens, we further investigated the function of host B7-H4 in the growth of a more immunogenic derivative, 4T1-12B, which is known to elicit strong anti-tumor CD8 T cell responses due to expression of a surrogate tumor-specific antigen, firefly luciferase. Notably, B7-H4 knockout hosts not only mounted greater tumor-associated anti-tumor T cell responses, but also displayed reduced tumors. Additionally, B7-H4-deficiency synergized with gemcitabine to further inhibit tumor growth, often leading to tumor eradication and the generation of protective T cell immunity. These findings imply that inhibition of host B7-H4 can enhance anti-tumor T cell immunity in immunogenic cancers, and can be combined with other anti-cancer therapies to further reduce tumor burden regardless of tumor-B7-H4 positivity.

Tracking larvae with molecular markers reveals high relatedness and early seasonal recruitment success in a partially spawning marine bivalve.

The partial synchronized spawning strategy adopted by some marine invertebrate broadcast-spawners can lead to the production of many distinct pools of larvae within a single reproductive cycle. Following the fate of these larval groups from birth to settlement with molecular markers might shed light on mechanisms regulating their population recruitment. Larvae and recruits of Mya arenaria, a partially spawning marine bivalve, were monitored and collected over 13 consecutive weeks during an entire reproductive cycle. Each sampled individual (n = 218) was sorted according to size (early veligers, late veligers, post-larval recruits) and genotyped at seven microsatellite loci for comparisons among samples and with adult reference samples (n = 270). While traditional differentiation statistics (e.g., pairwise Δ(ST), allelic richness) suggested the absence of sweepstakes reproductive success, the level of relatedness found within and among larvae and recruit samples suggested otherwise. Four samples out of ten were observed to have higher within-sample relatedness values than randomly expected, including the very first group of early veligers produced in the season (E1) and the last group of post-larvae who survived recruitment (P10). E1 individuals were also found to be more related than randomly expected to individuals of more than 80% of all other samples including the last surviving recruits (P8 and P10). These results suggest that the first larvae produced in the season were the most successful to survive recruitment. Results also show direct evidence for larval retention and demonstrate for the first time larval and post-larval kin aggregation in a marine bivalve.

Permanent Genetic Resources added to Molecular Ecology Resources Database 1 June 2011-31 July 2011.

This article documents the addition of 112 microsatellite marker loci and 24 pairs of single nucleotide polymorphism (SNP) sequencing primers to the Molecular Ecology Resources Database. Loci were developed for the following species: Agelaius phoeniceus, Austrolittorina cincta, Circus cyaneus, Circus macrourus, Circus pygargus, Cryptocoryne × purpurea Ridl. nothovar. purpurea, Mya arenaria, Patagioenas squamosa, Prochilodus mariae, Scylla serrata and Scytalopus speluncae. These loci were cross-tested on the following species: Cryptocoryne × purpurea nothovar. purpurea, Cryptocoryne affinis, Cryptocoryne ciliata, Cryptocoryne cordata var. cordata, Cryptocoryne elliptica, Cryptocoryne griffithii, Cryptocoryne minima, Cryptocoryne nurii and Cryptocoryne schulzei. This article also documents the addition of 24 sequencing primer pairs and 24 allele-specific primers or probes for Aphis glycines.