Intraepithelial macrophage infiltration is related to a high number of regulatory T cells and promotes a progressive course of HPV‐induced vulvar neoplasia

Abstract

Human papilloma virus (HPV)-induced usual-type vulvar intraepithelial neoplasia (uVIN) is infiltrated by myeloid cells but the type and role of these cells is unclear. We used triple immunofluorescent confocal microscopy to locate, identify and quantify myeloid cells based on their staining pattern for CD14, CD33 and CD163 in a cohort of 43 primary and 20 recurrent uVIN lesions, 21 carcinomas and 26 normal vulvar tissues. The progressive course of uVIN is characterized by an increase in both intraepithelial and stromal mature M1 and M2 macrophages. While the M2 macrophages outnumber M1 macrophages in healthy controls and uVIN, they are matched in number by M1 macrophages in cancer. Importantly, uVIN patients with a dense intraepithelial infiltration with mature CD141 macrophages (irrespective of M1 or M2 type) displayed approximately a six times higher risk to develop a recurrence and a high number of these cells constituted an independent prognostic factor for recurrence. In addition, a dense intraepithelial CD141 cell infiltration was associated with high numbers of intraepithelial CD41 Tregs and low numbers of stromal CD81TIM31 T cells. Patients with low numbers of intraepithelial CD141 cells and high numbers of stromal CD81TIM31 cells showed the best recurrence-free survival. These data clearly show the importance of the local immune response in HPV-induced vulvar neoplasia and may be of help in predicting the prognosis of patients or their response to immunotherapy.Usual-type vulvar intraepithelial neoplasia (uVIN) lesions are caused by a persistent high-risk human papilloma virus (HPV) infection (mainly HPV 16) and are characterized by high recurrences, a low spontaneous regression rate of 1.5% and a malignant potential of 3-4% in treated patients. [1][2][3] Treatment of uVIN lesions is indispensable since 80% of patients suffer from symptoms as pruritis and pain. 2-4 Conventional treatment consistent of potential disfiguring surgical interventions is associated with psychosexual problems and is increasingly replaced by either standardized immunotherapy with imiquimod or immunotherapy in experimental setting by therapeutic vaccination or photodynamic therapy, with promising clinical successes. [2][3][4][5][6][7][8] The incidence of hrHPV-induced dysplasia is increased in immunocompromised patients highlighting the essential role of the immune system in viral clearance. 9,10 Spontaneous regression of HPV is associated with systemic HPV-specific CD41 and CD81 immune responses, however in most of the patients with uVIN these T cell responses are either weak or absent. 11,12 In addition, the local innate immune cell environment is known to influence innate and adaptive immune responses in tumors. 13,14 Monocytes are innate immune cells which can differentiate into dendritic cells (DCs) or macrophages in response to local factors. 13 DCs process and present antigens to T cells, stimulate cytotoxicity of NK cells and initiate the adaptive immune response. 15 Studies of the microenvironment in uVIN revealed that ...

Distinct patterns of infiltrating CD8+ T cells in HPV+ and CD68 macrophages in HPV- oropharyngeal squamous cell carcinomas are associated with better clinical outcome but PD-L1 expression is not prognostic

“…With this rider, “M1 and M2 macrophages” are recruited to sites of inflammation with the overall effect resulting from the balance of types. In HPV¯OPSCC one might speculate a predominant infiltration of M1 macrophages known to exert an anti-tumour effect [33]. This theory is further strengthened by: 1) the observation of significantly higher cytotoxic T cell densities and 2) increased expression of PD-L1 in patients with higher macrophage densities.…”

Vaccination against Oncoproteins of HPV16 for Noninvasive Vulvar/Vaginal Lesions: Lesion Clearance Is Related to the Strength of the T-Cell Response

“…Individual variation between patients in immune and clinical response may be due to the individual differences in immune microenvironment (22,23). The selection of patients based on specific microenvironmental factors may increase clinical responsiveness in subsequent trials.…”

Long-term Survival and Clinical Benefit from Adoptive T-cell Transfer in Stage IV Melanoma Patients Is Determined by a Four-Parameter Tumor Immune Signature

“…The presence of T-cell and macrophage infiltrate in the tumor area and the expression of galectin-1, galectin-3, and galectin-9 by the tumor was analyzed using previously determined optimal antibody concentrations and immunofluorescence staining protocols as described before (19,20). Briefly, T-cell infiltrates were stained with antibodies to CD3, CD8, and FoxP3.…”