Distinct Patterns of Myeloid Cell Infiltration in Patients With hrHPV-Positive and hrHPV-Negative Penile Squamous Cell Carcinoma: The Importance of Assessing Myeloid Cell Densities Within the Spatial Context of the Tumor

Abstract

Comprehensive analysis of tumor infiltrating myeloid cells in the tumor microenvironment of penile squamous cell carcinoma (PSCC) is lacking. In this retrospective study, for the first time, PSCC resection specimens (N = 103) were annotated into the following compartments: intratumoral tumor (IT Tumor), intratumoral stroma (IT Stroma), peritumoral tumor (PT Tumor) and peritumoral stroma (PT Stroma) compartments. We then quantified CD14+, CD68+ and CD163+ myeloid cells within these compartments using an image analysis software and assessed their association with various clinical parameters, including high-risk human papillomavirus (hrHPV) status. In the total cohort, hrHPV status, grade of differentiation, age and tumor size were associated with myeloid cell densities. hrHPV+ tumors had higher infiltration rates of CD14+, CD68+ and CD163+ myeloid cells in the IT tumor compartment (p < 0.001, for all) compared to hrHPV− tumors. Furthermore, when examining the association between compartment-specific infiltration and differentiation grade, increased myeloid cell densities in the IT tumor compartment were associated with a more advanced histological grade (p < 0.001, for all). This association remained significant when the hrHPV− cohort (N = 60) was analyzed (CD14+ p = 0.001; CD68+ p < 0.001; CD163+ p = 0.004). Subgroup analysis in the hrHPV+ group (N = 43) showed that high infiltration rates of CD68+ and CD163+ cells in the PT tumor compartment were associated with lymph node (LN) metastasis (p = 0.031 and p = 0.026, respectively). Regarding the association between myeloid cell densities and disease-specific survival, the risk of death was found to decrease slightly as the number of myeloid cells in the IT tumor compartment increased (CD14+ p = 0.04; CD68+ p = 0.05; CD163+ p = 0.02). However, after adjusting for hrHPV, no independent association between myeloid densities and disease-specific survival were found. Altogether, these findings demonstrate the importance of assessing myeloid cell densities within the spatial context of the tumor. Further studies are needed to unravel the specific phenotype of myeloid cells residing in the different compartments, their effect on clinical parameters and the impact of hrHPV on the recruitment of myeloid cell populations in PSCC.

The Relationship between VEGF-C, TAM, and Lymph Node Metastasis in Oral Cancer

“…e density of lymphatic vessels, the number of TAMs and the expression of VEGF-C in the lymph node metastasis group were higher than those in the nonmetastasis group, and the Evidence-Based Complementary and Alternative Medicine density of lymphatic vessels, the number of TAMs and the expression of VEGF-C in paracancerous tissues in the metastasis group were higher than tumor tissues. With the development of oral cancer, VEGF-C affects macrophages to play a normal function, promotes the proliferation of tumor cells, and helps oral cancer cells to further invade and metastasize [22,23]. Higher TAMs numbers and higher expression levels of VEGF-C lead to more lymph node metastasis.…”

Immunotherapeutic Approaches for the Treatment of HPV-Associated (Pre-)Cancer of the Cervix, Vulva and Penis

“…However, the finding that Treg recruitment to TDLN appeared to precede both tumor invasion and subsequent M2 recruitment rather suggested a driving role for Tregs in tumor progression and an associated M2 macrophage influx [111]. No association was found between CD14+, CD68+, and CD163+ myeloid densities and survival in patients with PSCC [112].…”

“…It remains unclear whether differences in treatment outcomes exist between hrHPV− and hrHPV+ cervical, vulvar, and penile cancer patients treated with ICI. What is known is that hrHPV+ and hrHPV− tumors are two molecularly and immunologically distinct subgroups with different levels of immune cell infiltration and immunosuppression, and importantly, improved clinical outcome in HPV+ subgroups [37,84,112,[199][200][201]. Future studies should investigate if HPV status affects objective response rate or prognosis in ICI-treated patients.…”