Abstract
The host’s immune system plays a pivotal role in many tumor types, including squamous cell carcinomas (SCCs). We aim to identify immunological prognosticators for lymph node metastases (LNM) and disease-specific survival (DSS) in penile SCC. For this retrospective observational cohort study, penile SCC patients (n = 213) treated in the Netherlands Cancer Institute, were selected if sufficient formalin-fixed, paraffin-embedded tumor material was available. Analysis included previously described high-risk human papilloma virus (hrHPV) status, immunohistochemical scores for classical and non-classical human leukocyte antigen (HLA) class I, programmed death ligand-1 (PD-L1) expression, and novel data on tumor-infiltrating macrophages and cytotoxic an regulatory T-cells. Clinicopathological characteristics and extended follow-up were also included. Regression analyses investigated relationships of the immune parameters with LNM and DSS. In the total cohort, diffuse PD-L1 tumor-cell expression, CD163+ macrophage infiltration, non-classical HLA class I upregulation, and low stromal CD8+ T-cell infiltration were all associated with LNM. In the multivariable model, only tumor PD-L1 expression remained a significant predictor for LNM (odds ratio (OR) 2.8, p = 0.05). hrHPV negativity and diffuse PD-L1 tumor-cell expression were significantly associated with poor DSS and remained so upon correction for clinical parameters [hazard ratio (HR) 9.7, p < 0.01 and HR 2.8, p = 0.03]. The only immune factor with different expression in HPV+ and HPV− tumors was PD-L1, with higher PD-L1 expression in the latter (p = 0.03). In the HPV− cohort (n = 158), LNM were associated with diffuse PD-L1 tumor-cell expression, high intratumoral CD163+ macrophage infiltration, and low number of stromal CD8+ T-cells. The first two parameters were also linked to DSS. In the multivariable regression model, diffuse PD-L1 expression remained significantly unfavorable for DSS (HR 5.0, p < 0.01). These results emphasize the complexity of the tumor microenvironment in penile cancer and point toward several possible immunotherapy targets. Here described immune factors can aid risk-stratification and should be evaluated in clinical immunotherapy studies to ultimately lead to patient tailored treatment.
Highlights
Penile squamous cell carcinoma (SCC) is a rare disease with an incidence of less than 1/100,000 in Western countries [1, 2]
Patients were usually clinically followed for 5 years, after that, patient status was sometimes available through municipal administration
disease-specific survival (DSS) was better in high-risk human papilloma virus (hrHPV)+ patients in comparison to hrHPV− patients, with 2 and 27 penile cancer
Summary
Penile squamous cell carcinoma (SCC) is a rare disease with an incidence of less than 1/100,000 in Western countries [1, 2]. The prognosis for early stage penile cancer patients is good (5-year survival without lymphogenic spread is 96%) but worsens gradually with presence of lymph node metastases (LNM) [2, 3]. Surgery is the mainstay of penile cancer treatment, for both primary tumors and LNM. In advanced stages (e.g., pelvic lymph node involvement or irresectable disease) multimodal treatment is necessary, mostly in the form of neoadjuvant chemotherapy or adjuvant radiation [4]. In 20–50% of the patients, penile SCC is induced by a persistent infection with high-risk human papilloma virus (hrHPV) [5, 6]. Patients with hrHPV+ tumors have a better disease-specific survival (DSS) than patients with hrHPV− tumors (5-year DSS of 96 vs 82% respectively) [7]
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