AUTHOR=R. S. Jayshree 

TITLE=The Immune Microenvironment in Human Papilloma Virus-Induced Cervical Lesions—Evidence for Estrogen as an Immunomodulator

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 11 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2021.649815

DOI=10.3389/fcimb.2021.649815

ISSN=2235-2988

ABSTRACT=Globally, Human Papilloma Virus (HPV) infection is a common sexually transmitted disease. However, most of the infections eventually resolve aided by the body’s efficient cell mediated immune response. In the vast majority of the small group of patients who develop overt disease too, it is the immune response which culminates in regression of lesions. It is therefore a rarity that persistent infection by high risk genotypes of HPV compounded by other risk factors progresses through precancer (various grades of cervical intraepithelial neoplasias - CIN) to cervical cancer (CxCa). Hence, although CxCa is a rare end result of HPV infection, the latter is nevertheless causally linked to >90% of cancer. The three ‘Es’ of cancer immunoediting viz. elimination, equilibrium and escape come into vogue during the gradual evolution of CIN I to CxCa. Both cell intrinsic and extrinsic mechanisms operate to eliminate virally infected cells:  cell extrinsic players are antitumor/antiviral effectors like Th1 subset of CD4+ T cells, CD8+ cytotoxic T cells, NK cells etc.; and protumorigenic/immunosuppressive cells like regulatory T cells (Tregs), Myeloid Derived Suppressor Cells (MDSCs), type 2 macrophages etc. And accordingly, when immunosuppressive cells overpower the effectors e.g. in high grade lesions like CIN 2 or 3, the scale is tilted towards immune escape and the disease progresses to cancer. Estrogen (E2) has long been considered as a co-factor in cervical carcinogenesis. In addition to the gonads, the peyer’s patches in the gut synthesize E2. Over and above local production of the hormone in the tissues, E2 metabolism by the gut microbiome: estrobolome versus tryptophan non-metabolizing microbiome, regulates free E2 levels in the intestine and extraintestinal mucosal sites. Elevated tissue levels of the hormone serve more than one purpose: besides a direct growth promoting action on cervical epithelial cells, E2 acting genomically via ERa also boosts the function of the stromal and infiltrating immunosuppressive cells viz. Tregs, MDSCs and carcinoma associated fibroblasts. Hence as a corollary, therapeutic repurposing of Selective Estrogen Receptor Disruptors or aromatase inhibitors could be useful for modulating immune function in cervical precancer/cancer. The immunomodulatory role of E2 in HPV mediated cervical lesions is reviewed.