PD-L1/PD1 Expression, Composition of Tumor-Associated Immune Infiltrate, and HPV Status in Conjunctival Squamous Cell Carcinoma

Abstract

PURPOSE. Conjunctival squamous cell carcinoma (SCC), a type of ocular surface neoplasia, is primarily treated by surgical resection and topical immuno-or chemotherapy. Metastatic disease may be treated with systemic chemo-or immunotherapy, albeit with variable response. The purpose of this study was to determine whether immune checkpoint blockade might be considered in the management of conjunctival SCC. METHODS. In this retrospective study, we evaluated tumor programmed death-ligand 1 (PD-L1) expression, high-risk human papillomavirus (HPV) status, and immunohistochemical expression of cluster of differentiation 3 (CD3), cluster of differentiation 8 (CD8), and programmed death 1 (PD1) in tumor-associated immune infiltrate in a series of 31 conjunctival SCCs. RESULTS. PD-L1 expression in ‡1% of tumor cells was noted in 14 conjunctival SCCs (47%) and was more prevalent in invasive than in situ SCC and among tumors with higher American Joint Committee on Cancer (AJCC) T category (‡T3 versus T2). The density of CD3-positive T cells was higher in primary than recurrent tumors and higher in invasive than in situ tumors. Density of CD3-positive and CD8-positive T cells was higher in higher AJCC stage tumors. Density of CD8-positive T cells was higher in HPV-positive than HPV-negative tumors. PD-L1 expression correlated with a higher density of CD3-, CD8-, and PD1-positive cells in the tumor-associated immune infiltrate but not with HPV status. CONCLUSIONS. Our findings demonstrate that PD-L1 is expressed in almost half of conjunctival SCCs. The density of tumor-associated immune cells correlated with invasive SCC, stage, and HPV status in conjunctival SCC. Our findings support further studies to establish the potential application of immune checkpoint blockade in the management of conjunctival SCC.

Human papillomavirus infection plays a role in conjunctival squamous cell carcinoma: a systematic review and meta‐analysis of observational studies

“…The studies comprise a total of 1410 cases and 939 controls published between 1986 and 2019 (McDonnell et al 1986; McDonnell et al 1989; Lauer et al 1990; McDonnell et al 1992; Adachi et al 1995; Saegusa et al 1995; Waddell et al 1996; Karcioglu & Issa 1997; Nakamura et al 1997; Tabrizi et al 1997; Dushku et al 1999; Palazzi et al 2000; Toth et al 2000; Eng et al 2002; Scott et al 2002; Tulvatana et al 2003; Ateenyi‐Agaba et al 2004; Moubayed et al 2004; Jung et al 2006; Kuo et al 2006; Tornesello et al 2006; Sen et al 2007; Auw‐Haedrich et al 2008; de Koning et al 2008; Guthoff et al 2009; Manderwad et al 2009; Ateenyi‐Agaba et al 2010; Asadi‐Amoli et al 2011; Peralta et al 2011; Chauhan et al 2012; Carrilho et al 2013; Woods et al 2013; Galor et al 2015; Afrogheh et al 2016; Moyer et al 2018; Griffin et al 2019; Nagarajan et al 2019; Ramberg et al 2019; Shrestha et al 2019). All studies included in the systematic review investigated patients with a histopathological diagnosis of CIN ( n = 468 patients) or conjunctival SCC ( n = 570 patients), or unspecified as ocular surface squamous neoplasia ( n = 372).…”

“…DNA in situ hybridization (Saegusa et al 1995; Nakamura et al 1997; Scott et al 2002; Moubayed et al 2004; Manderwad et al 2009; Galor et al 2015; Afrogheh et al 2016) and immunohistochemistry using HPV capsid antibodies (McDonnell et al 1986; Sen et al 2007; Guthoff et al 2009; Woods et al 2013) have also been used. The presence of HPV E6 and E7 mRNA, and thereby the presence of actively transcribing viruses, was investigated in four studies, and all four studies detected viral mRNA expression within the tumour tissue (Scott et al 2002; Griffin et al 2019; Nagarajan et al 2019; Ramberg et al 2019). Fourteen studies used a combination of methods, including the surrogate marker p16, for HPV detection.…”

Advanced ocular surface squamous cell carcinoma (OSSC): long-term follow-up

“…Customized adjuvant treatments should always be planned, including EBRT, brachytherapy, local, and also systemic chemotherapy. Cemiplimab, a PD1 inhibitor which was recently approved for the treatment of cutaneous SCC, has been suggested for OSCC patients and could be considered in the therapeutic strategy [19][20][21].…”

Advances in the management of eyelid tumors

“…Cancer cells overexpress PD-L1 which binds to a PD-1 receptor on T cells, inhibiting their activation and thereby suppressing effective T-cell cytotoxic response against a tumor antigen. 13 Ingenol mebutate, a plant derivative from the sap of Euphorbia peplus, in a dose of 150 ug/g gel, has been FDA approved for treatment of actinic keratosis and squamous cell carcinomas. 14 It affects the PKC/MEK/ERK signalling pathway resulting in a reduction in the long-term viability of the cells and induction of programmed cancer cell death.…”