Immune Response Modulation by Tumor-Secreted Glycosphingolipids

Although originally considered merely structural components of cellular membranes, glycosphingolipids (GSL) arenow recognized as having critical effects on cellular physiology, including proliferation, differentiation, viraltransformation and ontogenesis. In addition, a vast majority of human cancers have modified GSL compositioncompared to parental normal cells. These modifications may contribute to both tumor survival and exert strikingeffects on anti-tumor immunity. In this review, we discuss mechanisms of immune modulation by tumor-secreted GSL.Fil: Lardone, Ricardo Dante. John Wayne Cancer Institute at Providence Saint John’s Health Center. Santa Monica; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Cely, Ingrid. John Wayne Cancer Institute at Providence Saint John’s Health Center. Santa Monica; Estados UnidosFil: Sieling, Peter A.. John Wayne Cancer Institute at Providence Saint John’s Health Center. Santa Monica; Estados UnidosFil: Lee, Delphine. John Wayne Cancer Institute at Providence Saint John’s Health Center. Santa Monica; Estados Unido

Spitzer Mid-to-Far-Infrared Flux Densities of Distant Galaxies

We study the infrared (IR) properties of high-redshift galaxies using deep Spitzer 24, 70, and 160 micron data. Our primary interest is to improve the constraints on the total IR luminosities, L(IR), of these galaxies. We combine the Spitzer data in the southern Extended Chandra Deep Field with a K-band-selected galaxy sample and photometric redshifts from the Multiwavelength Survey by Yale-Chile. We used a stacking analysis to measure the average 70 and 160 micron flux densities of 1.5 < z < 2.5 galaxies as a function of 24 micron flux density, X-ray activity, and rest-frame near-IR color. Galaxies with 1.5 < z < 2.5 and S(24)=53-250 micro-Jy have L(IR) derived from their average 24-160 micron flux densities within factors of 2-3 of those derived from the 24 micron flux densities only. However, L(IR) derived from the average 24-160 micron flux densities for galaxies with S(24) > 250 micro-Jy and 1.5 < z < 2.5 are lower than those derived using only the 24 micron flux density by factors of 2-10. Galaxies with S(24) > 250 micro-Jy have S(70)/S(24) flux ratios comparable to sources with X-ray detections or red rest-frame IR colors, suggesting that warm dust possibly heated by AGN may contribute to the high 24 micron emission. Based on the average 24-160 micron flux densities, nearly all 24 micron-selected galaxies at 1.5 < z < 2.5 have L(IR) < 6 x 10^12 solar luminosities, which if attributed to star formation corresponds to < 1000 solar masses per year. This suggests that high redshift galaxies may have similar star formation efficiencies and feedback processes as local analogs. Objects with L(IR) > 6 x 10^12 solar luminosities are quite rare, with a surface density ~ 30 +/- 10 per sq. deg, corresponding to ~ 2 +/- 1 x 10^-6 Mpc^-3 over 1.5 < z < 2.5.Comment: Accepted for Publication in ApJ. AASTeX format. 34 pages, 12 figures. Updated references and other small textual revision

Publisher Correction: An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

BCG hydrogel promotes CTSS-mediated antigen processing and presentation, thereby suppressing metastasis and prolonging survival in melanoma.

BACKGROUND The use of intralesional Mycobacterium bovis BCG (intralesional live BCG) for the treatment of metastatic melanoma resulted in regression of directly injected, and occasionally of distal lesions. However, intralesional-BCG is less effective in patients with visceral metastases and did not significantly improve overall survival. METHODS We generated a novel BCG lysate and developed it into a thermosensitive PLGA-PEG-PLGA hydrogel (BCG hydrogel), which was injected adjacent to the tumor to assess its antitumor effect in syngeneic tumor models (B16F10, MC38). The effect of BCG hydrogel treatment on contralateral tumors, lung metastases, and survival was assessed to evaluate systemic long-term efficacy. Gene expression profiles of tumor-infiltrating immune cells and of tumor-draining lymph nodes from BCG hydrogel-treated mice were analyzed by single-cell RNA sequencing (scRNA-seq) and CD8+ T cell receptor (TCR) repertoire diversity was assessed by TCR-sequencing. To confirm the mechanistic findings, RNA-seq data of biopsies obtained from in-transit cutaneous metastases of patients with melanoma who had received intralesional-BCG therapy were analyzed. RESULTS Here, we show that BCG lysate exhibits enhanced antitumor efficacy compared to live mycobacteria and promotes a proinflammatory tumor microenvironment and M1 macrophage (MΦ) polarization in vivo. The underlying mechanisms of BCG lysate-mediated tumor immunity are dependent on MΦ and dendritic cells (DCs). BCG hydrogel treatment induced systemic immunity in melanoma-bearing mice with suppression of lung metastases and improved survival. Furthermore, BCG hydrogel promoted cathepsin S (CTSS) activity in MΦ and DCs, resulting in enhanced antigen processing and presentation of tumor-associated antigens. Finally, BCG hydrogel treatment was associated with increased frequencies of melanoma-reactive CD8+ T cells. In human patients with melanoma, intralesional-BCG treatment was associated with enhanced M1 MΦ, mature DC, antigen processing and presentation, as well as with increased CTSS expression which positively correlated with patient survival. CONCLUSIONS These findings provide mechanistic insights as well as rationale for the clinical translation of BCG hydrogel as cancer immunotherapy to overcome the current limitations of immunotherapies for the treatment of patients with melanoma