Immunometabolic Determinants of Chemoradiotherapy Response and Survival in Head and Neck Squamous Cell Carcinoma.

Tumor immune microenvironment and tumor metabolism are major determinants of chemoradiotherapy response. The interdependency and prognostic significance of specific immune and metabolic phenotypes in head and neck squamous cell carcinoma (HNSCC) were assessed and changes in reactive oxygen species were evaluated as a mechanism of treatment response in tumor spheroid/immunocyte co-cultures. Pretreatment tumor biopsies were immunohistochemically characterized in 73 HNSCC patients treated by definitive chemoradiotherapy and correlated with survival. The prognostic significance of CD8A, GLUT1, and COX5B gene expression was analyzed within The Cancer Genome Atlas database. HNSCC spheroids were co-cultured in vitro with peripheral blood mononuclear cells (PBMCs) in the presence of the glycolysis inhibitor 2-deoxyglucose and radiation treatment followed by PBMC chemotaxis determination via fluorescence microscopy. In the chemoradiotherapy-treated HNSCC cohort, mitochondrial-rich (COX5B) metabolism correlated with increased and glucose-dependent (GLUT1) metabolism with decreased intratumoral CD8/CD4 ratios. High CD8/CD4, together with mitochondrial-rich or glucose-independent metabolism, was associated with improved short-term survival. The Cancer Genome Atlas analysis confirmed that patients with a favorable immune and metabolic gene signature (high CD8A, high COX5B, low GLUT1) had improved short- and long-term survival. In vitro, 2-deoxyglucose and radiation synergistically up-regulated reactive oxygen species-dependent PBMC chemotaxis to HNSCC spheroids. These results suggest that glucose-independent tumor metabolism is associated with CD8-dominant antitumor immune infiltrate, and together, these contribute to improved chemoradiotherapy response in HNSCC.

Multimodal immune cell phenotyping in GI biopsies reveals microbiome-related T cell modulations in human GvHD.

Acute graft-versus-host disease (aGvHD) is a significant complication after allogeneic hematopoietic stem cell transplantation (aHSCT), but major factors determining disease severity are not well defined yet. By combining multiplexed tissue imaging and single-cell RNA sequencing on gastrointestinal biopsies from aHSCT-treated individuals with fecal microbiome analysis, we link high microbiome diversity and the abundance of short-chain fatty acid-producing bacteria to the sustenance of suppressive regulatory T cells (Tregs). Furthermore, aGvHD severity strongly associates with the clonal expansion of mainly CD8 T cells, which we find distributed over anatomically distant regions of the gut, persistent over time, and inversely correlated with the presence of suppressive Tregs. Overall, our study highlights the pathophysiological importance of expanded CD8 T cell clones in the progression of aGvHD toward more severe clinical manifestations and strongly supports the further development of microbiome interventions as GvHD treatment via repopulation of the gut Treg niche to suppress inflammation.

Immunologic and metabolic characteristics of HPV-negative and HPV-positive head and neck squamous cell carcinomas are strikingly different.

An HPV infection is involved in the etiology of about 25 % of head and neck squamous cell carcinomas (HNSCC). It has been postulated that a strong antitumoral immune response in HPV-positive tumors represents an important underlying mechanism for their good response to therapy. Recently, the Warburg phenomenon has returned to the center of attention because it affects antitumoral immune response and response to therapy. Accumulation of tumor cell-derived lactate inhibits cytotoxic T cells, as these, analogous to cancer cells, depend on glycolysis and lactate secretion for fulfillment of energy needs. Sparse information exists on the Warburg effect in HNSCC. This study aimed to characterize the metabolic and immunological features of HPV-negative and HPV-positive HNSCC. An immunohistochemical analysis of oropharyngeal carcinomas showed an enhanced antitumoral immune response (CD8/CD4 ratio) together with increased levels of proteins involved in transmembranous metabolite transportation (GLUT1 and CD147) and respiratory metabolism (COX5B) in HPV-positive tumors as compared to HPV-negative tumors. mRNA and Western blot analyses of an HPV-positive and HPV-negative HNSCC cell line revealed metabolic characteristics similar to the in vivo situation. Additionally, the HPV-negative cell line showed stronger extracellular lactate accumulation. In contrast, the HPV-positive cell line presented with better adaption to lactic acidosis suggesting an ability to metabolize lactate. Our results indicate that HPV-positive and HPV-negative carcinomas do not only differ in terms of tumor immune microenvironment, but also in terms of tumor metabolism, characterized by an increased glucose and respiratory metabolism together with decreased lactate accumulation in HPV-positive HNSCC. Therefore, targeting metabolic pathways could represent a promising adjunct in the therapy of HPV-positive HNSCC.