Kidacki Michal, Cho Christina, Lopez-Giraldez Francesc, Huang Baozhu, He Jianwei, Gaule Patricia, Chen Lieping, Vesely Matthew D
Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.
Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA.
J Invest Dermatol. 2025 Feb 19. doi: 10.1016/j.jid.2025.01.030.
Cutaneous squamous cell carcinoma (cSCC) is one of the most common human cancers, with an estimated death rate approaching or exceeding that of melanoma. Immune inhibitory receptor antagonism through the blockade of PD-1 or its ligand, PD-L1, has revolutionized the treatment of cSCC; however, approximately half of patients still fail to respond. The inhibitory receptor PD-1H (also known as VISTA) controls T-cell and myeloid cell functions in preclinical cancer studies. Currently, cancer clinical trials using anti-VISTA-blocking antibodies are ongoing. We sought to determine the extent of VISTA expression in cSCCs and to correlate its expression with PD-L1 expression. Using multiplexed quantitative immunofluorescence of primary cSCC tissues (n = 76), we found that VISTA was expressed in 48% of cSCCs and that PD-L1 was expressed in 58% of cSCCs. We found that high VISTA expression, more than PD-L1 expression, correlated with greater T-cell infiltration and activation, as measured by the proliferation marker Ki-67 and the cytotoxic marker granzyme B. Furthermore, there was no significant correlation between VISTA and PD-L1 coexpression within the same cSCCs, suggesting that individual tumors have distinct immunosuppressive microenvironments. These findings provide a rationale for the targeting of VISTA in cSCC immunotherapy.
皮肤鳞状细胞癌（cSCC）是最常见的人类癌症之一，其估计死亡率接近或超过黑色素瘤。通过阻断PD-1或其配体PD-L1来拮抗免疫抑制受体，彻底改变了cSCC的治疗方式；然而，仍有大约一半的患者没有反应。在临床前癌症研究中，抑制性受体PD-1H（也称为VISTA）可控制T细胞和髓样细胞功能。目前，使用抗VISTA阻断抗体的癌症临床试验正在进行中。我们试图确定VISTA在cSCC中的表达程度，并将其表达与PD-L1表达相关联。通过对原发性cSCC组织（n = 76）进行多重定量免疫荧光分析，我们发现48%的cSCC表达VISTA，58%的cSCC表达PD-L1。我们发现，与PD-L1表达相比，高VISTA表达与更高的T细胞浸润和激活相关，这通过增殖标志物Ki-67和细胞毒性标志物颗粒酶B来衡量。此外，在同一cSCC中，VISTA和PD-L1的共表达之间没有显著相关性，这表明单个肿瘤具有不同的免疫抑制微环境。这些发现为在cSCC免疫治疗中靶向VISTA提供了理论依据。
