Activities of stromal and immune cells in HPV-related cancers

Abstract

The immune system is composed of immune as well as non-immune cells. As this system is a well-established component of human papillomavirus- (HPV)-related carcinogenesis, high risk human papillomavirus (hrHPV) prevents its routes and mechanisms in order to cause the persistence of infection. Among these mechanisms are those originated from stromal cells, which include the cancer-associated fibroblasts (CAFs), the myeloid-derived suppressor cells (MDSCs) and the host infected cells themselves, i.e. the keratinocytes. These types of cells play central role since they modulate immune cells activities to create a prosperous milieu for cancer development, and the knowledge how such interactions occur are essential for prognostic assessment and development of preventive and therapeutic approaches. Nevertheless, the precise mechanisms are not completely understood, and this lack of knowledge precluded the development of entirely efficient immunotherapeutic strategies for HPV-associated tumors. As a result, an intense work for attaining how host immune response works, and developing of effective therapies has been applied in the last decade. Based on this, this review aims to discuss the major mechanisms of immune and non-immune cells modulated by hrHPV and the potential and existing immunotherapies involving such mechanisms in HPV-related cancers. It is noticed that the combination of immunotherapies has been demonstrated to be essential for obtaining better results, especially because the possibility of increasing the modulating capacity of the HPV-tumor microenvironment has been shown to be central in strengthening the host immune system.

The role of the innate and adaptive immune response in HPV‐associated oropharyngeal squamous cell carcinoma

“…In particular, cancer associated fibroblasts (CAFs) appear to play a major role in driving immunosuppression, cell growth, and metastasis in HPV‐associated cancers including OPSCC and cervical . CAFs facilitate HPV‐positive cervical cancer cell‐mediated TGFβ1 and matrix metalloproteinase 7 (MMP7) secretion, contributing to tumor progression . The mechanisms involved in CAF‐facilitated HPV‐positive HNSCC progression are limited.…”

“…The mechanisms involved in CAF‐facilitated HPV‐positive HNSCC progression are limited. Through mechanisms that are not entirely clear, normal fibroblasts transition into a pro‐inflammatory state . This results in fibroblasts gaining a pro‐inflammatory gene expression signature which includes expression of a variety of factors such as chemokines (CXCL1, CXCL2, CXCL5), interleukins (IL‐1B, IL‐6), and cxyclooxygenase‐2 gene .…”

“…HPV‐infected cells, in addition to keratinocytes attracted to the tumor, secrete a milieu of chemokines and cytokines that induce normal fibroblasts mutation into CAFs. Factors implicated in this conversion include IL‐1β, IL‐6, IL‐8, TGF‐β, CXCL12, and bFGF . CAFs then act to drive and maintain transformation of HPV‐positive cells into neoplastic cells resulting in tumor growth, invasion, and progression.…”

“…Although there are numerous types of macrophages, in general, two main phenotypes, inflammatory/classic M1 and tumor‐associated macrophages (TAM) M2, have been described pertaining to HPV‐associated cancers . TAMs appear to have a role in tumor progression by boosting Th2 response, inhibiting CD4+ and CD8+ T cell responses and secreting VEGF and other proangiogenic factors . They have been shown to secrete pro‐tumorigenic and angiogenic factors such as EGF and VEGF as well as anti‐inflammatory cytokines such as IL‐10 and TGFβ .…”

Mining the potential prognostic value of synaptosomal-associated protein 25 (SNAP25) in colon cancer based on stromal-immune score

“…Stromal cells and immune cells form the major fraction of colon cancer tissue and are associated with tumor progress, inflammatory and metabolic disorders ( Ghesquière et al, 2014 ; Nilendu et al, 2018 ). An increasing amount of studies have highlighted the importance of stromal cells and immune cells in cancer biology and microenvironment across different types of cancers ( Barros Jr et al., 2018 ; Garcia-Gomez, Rodríguez-Ubreva & Ballestar, 2018 ; Zhan et al, 2017 ). ESTIMATE is a new method that infers stromal and immune cells in malignant tumors using gene expression signatures ( Yoshihara et al, 2013 ), and has been conducted in acute myeloid leukemia ( Yan et al, 2019 ), gastric cancer ( Wang, Wu & Chen, 2019 ), and glioblastoma ( Jia et al, 2018 ).…”