G-CSF Is a Novel Mediator of T-Cell Suppression and an Immunotherapeutic Target for Women with Colon Cancer.

PURPOSE: G-CSF enhances colon cancer development. This study defines the prevalence and effects of increased G-CSF signaling in human colon cancers and investigates G-CSF inhibition as an immunotherapeutic strategy against metastatic colon cancer. EXPERIMENTAL DESIGN: Patient samples were used to evaluate G-CSF and G-CSF receptor (G-CSFR) levels by IHC with sera used to measure G-CSF levels. Peripheral blood mononuclear cells were used to assess the rate of G-CSFR+ T cells and IFNγ responses to chronic ex vivo G-CSF. An immunocompetent mouse model of peritoneal metastasis (MC38 cells in C57Bl/6J) was used to determine the effects of G-CSF inhibition (αG-CSF) on survival and the tumor microenvironment (TME) with flow and mass cytometry. RESULTS: In human colon cancer samples, the levels of G-CSF and G-CSFR are higher compared to normal colon tissues from the same patient. High patient serum G-CSF is associated with increases in markers of poor prognosis, (e.g., VEGF, IL6). Circulating T cells from patients express G-CSFR at double the rate of T cells from controls. Prolonged G-CSF exposure decreases T cell IFNγ production. Treatment with αG-CSF shifts both the adaptive and innate compartments of the TME and increases survival (HR, 0.46; P = 0.0237) and tumor T-cell infiltration, activity, and IFNγ response with greater effects in female mice. There is a negative correlation between serum G-CSF levels and tumor-infiltrating T cells in patient samples from women. CONCLUSIONS: These findings support G-CSF as an immunotherapeutic target against colon cancer with greater potential benefit in women.

The role of sex in the innate and adaptive immune environment of metastatic colorectal cancer.

BACKGROUND: Women with colorectal cancer (CRC) have a significant survival advantage over men. Sex influences on the tumour microenvironment (TME) are not well characterised, despite the importance of immune response in CRC. We hypothesised that sex-divergent immune responses could contribute to survival. METHODS: Using a murine model of metastatic CRC, we examined T cells, macrophages, and cytokines locally and systemically. TME and serum cytokines were measured by multiplex bead-based arrays, while FCA was used to identify cells and phenotypes. IHC provided spatial confirmation of T cell infiltration. RESULTS: Females had increased survival and T cell infiltration. CD8, CD4 and Th2 populations correlated with longer survival. Males had increased serum levels of chemokines and inflammation-associated cytokines. Within the TME, males had lower cytokine levels than females, and a shallower cytokine gradient to the periphery. Female tumours had elevated IL-10+ macrophages, which correlated with survival. CONCLUSIONS: These data demonstrate survival-associated differences in the immune response of males and females to metastatic CRC. Females showed changes in cytokine production accompanied by increased immune cell populations, biased toward Th2-axis phenotypes. Key differences in the immune response to CRC correlated with survival in this model. These differences support a multi-faceted shift across the TME.

Object-based attention modulates the discrimination of level increments in stop-consonant noise bursts.

This study tested the hypothesis that object-based attention modulates the discrimination of level increments in stop-consonant noise bursts. With consonant-vowel-consonant (CvC) words consisting of an ≈80-dB vowel (v), a pre-vocalic (Cv) and a post-vocalic (vC) stop-consonant noise burst (≈60-dB SPL), we measured discrimination thresholds (LDTs) for level increments (ΔL) in the noise bursts presented either in CvC context or in isolation. In the 2-interval 2-alternative forced-choice task, each observation interval presented a CvC word (e.g., /pæk/ /pæk/), and normal-hearing participants had to discern ΔL in the Cv or vC burst. Based on the linguistic word labels, the auditory events of each trial were perceived as two auditory objects (Cv-v-vC and Cv-v-vC) that group together the bursts and vowels, hindering selective attention to ΔL. To discern ΔL in Cv or vC, the events must be reorganized into three auditory objects: the to-be-attended pre-vocalic (Cv-Cv) or post-vocalic burst pair (vC-vC), and the to-be-ignored vowel pair (v-v). Our results suggest that instead of being automatic this reorganization requires training, in spite of using familiar CvC words. Relative to bursts in isolation, bursts in context always produced inferior ΔL discrimination accuracy (a context effect), which depended strongly on the acoustic separation between the bursts and the vowel, being much keener for the object apart from (post-vocalic) than for the object adjoining (pre-vocalic) the vowel (a temporal-position effect). Variability in CvC dimensions that did not alter the noise-burst perceptual grouping had minor effects on discrimination accuracy. In addition to being robust and persistent, these effects are relatively general, evincing in forced-choice tasks with one or two observation intervals, with or without variability in the temporal position of ΔL, and with either fixed or roving CvC standards. The results lend support to the hypothesis.