Extricating human tumour immune alterations from tissue inflammation

Abstract

Immunotherapies have achieved remarkable successes in the treatment of cancer, but major challenges remain1,2. An inherent weakness of current treatment approaches is that therapeutically targeted pathways are not restricted to tumours, but are also found in other tissue microenvironments, complicating treatment3,4. Despite great efforts to define inflammatory processes in the tumour microenvironment, the understanding of tumour-unique immune alterations is limited by a knowledge gap regarding the immune cell populations in inflamed human tissues. Here, in an effort to identify such tumour-enriched immune alterations, we used complementary single-cell analysis approaches to interrogate the immune infiltrate in human head and neck squamous cell carcinomas and site-matched non-malignant, inflamed tissues. Our analysis revealed a large overlap in the composition and phenotype of immune cells in tumour and inflamed tissues. Computational analysis identified tumour-enriched immune cell interactions, one of which yields a large population of regulatory T (Treg) cells that is highly enriched in the tumour and uniquely identified among all haematopoietically-derived cells in blood and tissue by co-expression of ICOS and IL-1 receptor type 1 (IL1R1). We provide evidence that these intratumoural IL1R1+ Treg cells had responded to antigen recently and demonstrate that they are clonally expanded with superior suppressive function compared with IL1R1− Treg cells. In addition to identifying extensive immunological congruence between inflamed tissues and tumours as well as tumour-specific changes with direct disease relevance, our work also provides a blueprint for extricating disease-specific changes from general inflammation-associated patterns.

Recent Advances in CXCL12/CXCR4 Antagonists and Nano-Based Drug Delivery Systems for Cancer Therapy

“…Chronic inflammation can initiate and contribute to the development of tumors. In tumor tissue, certain inflammatory factors, such as mononuclear inflammatory cells (MICs) and myeloid-derived suppressor cells (MDSCs), can cause immunosuppression and thus promote tumor development [ 34 ]. Meanwhile, neutrophils, as the predominant leukocytes, often show contradictory therapeutic effects on cancers.…”

A path forward to improving the specificity of immunotherapies

“…Overall, our study revealed that cell subsets and biomarkers often associated with the tumour microenvironment are also highly abundant in inflamed tissue. For example, the immune infiltrate in both tissues had an equal abundance of PD‐1‐expressing CD8 T cells 1 . Of note, we observed in an earlier study that PD‐1‐expressing T cells were widely found even in healthy human oral mucosal tissues 2 .…”

“…For example, the immune infiltrate in both tissues had an equal abundance of PD‐1‐expressing CD8 T cells. 1 Of note, we observed in an earlier study that PD‐1‐expressing T cells were widely found even in healthy human oral mucosal tissues. 2 These observations illustrate that cellular targets for the most common ICI treatment approach, antibodies against PD‐1 (pembrolizumab, nivolumab and cemiplimab) and PD‐L1 (atezolizumab, avelumab and durvalumab), are present in healthy and inflamed human tissues.…”

Protein profiling of breast carcinomas reveals expression of immune-suppressive factors and signatures relevant to patient outcome

“…Nevertheless, current cancer therapies are lacking a more personalized approach and long-term therapy resistance has become a focus of current research [3, 4]. Novel insights on the establishment, interaction, and control of the tumour immune microenvironment (TIME) have drawn a more comprehensive picture of factors that might account for treatment failure or severe side effects [3, 5]. The detection of tumour infiltrating lymphocytes (TIL) is seen as a major prognostic factor in different carcinomas and has been suggested as a routine pathological evaluation [6, 7].…”