Dissection of the heterogeneity of tumour microenvironment facilitates therapies of cancers

Abstract

Tumor microenvironment (TME) has been recognized as one of the important resources of tumor heterogeneity. The dissection of the TME by taking the advantage of high throughput data such as single-cell RNA sequencing (scRNA-seq) data has facilitated cancer research and helped to identify determinants of drug response, including immunotherapy. Even though immunotherapy such as immune checkpoint blockade (ICB) has facilitated cancer therapies, most patients do not response to ICB. What determines the response to ICB and how it is affected by TME is not well-illustrated yet. A subgroup of colorectal cancer (CRC) patients was highly immune infiltrated but had poor prognosis. I, therefore, suspected some potential factors might contribute to this phenotype. The results revealed that transposable element (TE) expression was related to immune cell infiltration and predictive of prognosis in CRC. Tumours with the highest TE expression score showed increased immune cell infiltration with upregulation of interferon (IFN) signalling pathways and downstream activation of IFN-simulated genes, which further triggered expression of PD-L1 in immune cells rather than tumour cells. This work addressed the potential immune evasion driven by TE. Immunotherapy has revolutionized the treatment of multiple cancers. While cancer morbidity increased with age and age-associated changes in immune function have been well characterized, age-induced differences in TME and their influences on the response to immunotherapy remain unknown. The results revealed that aged individuals responded more efficiently to ICB treatment at the pan-cancer level. Further Cox regression screening on age revealed that patients above 47 years of age responded better and had longer progression-free survival than younger counterparts. scRNA-seq data analysis revealed the accumulation of immune response and chronic inflammation with increasing age in multiple cancers, including lung and gastrointestinal cancers. This work highlights sufficient ICB response in older patients. The TME is found to be reprogrammed during cancer metastasis which also influences therapy response. Liver metastasis is commonly observed in pancreatic ductal adenocarcinoma (PDAC). To dissect the heterogeneity of PDAC upon metastasis, I analyzed integrated data of mass cytometry and scRNA-seq data and revealed that the proportion of tumor-resident CD4+/CD8+ T cells was decreased in metastasis PDAC while the proportion of CD73+ macrophage was increased, which were also validated using scRNA-seq data. This work revealed the metastasis-specific phenotypes in TME of PDAC. Together, I linked the phenotypes of cancers such as prognosis, aging, and metastasis with TME, addressing the importance of TME during cancer progression and revealing some underlying determinants, facilitating more effective cancer therapy.