Immune cell patterns before and after neoadjuvant immune checkpoint blockade combined with chemoradiotherapy in locally advanced esophageal squamous cell carcinoma

Abstract

Abstract Background: Neoadjuvant immune checkpoint blockade (ICB) combined with chemoradiotherapy offers high pathologic complete response (pCR) rate for patients with locally advanced esophageal squamous cell carcinomas (ESCC). But the dynamic tumor immune microenvironment modulated by such neoadjuvant therapy remains unclear. Patients and methods: A total of 41 patients with locally advanced ESCC were recruited. Paired matched pre- and post-treatment tissues were obtained for fluorescent multiplex immunohistochemistry (mIHC) and IHC analyses. The densities and spatial distributions of immune cells were determined by HALO modules. Results: The differences of immune cell patterns before and after treatment were investigated, using matched paired tissues of 41 patients who received R0 resection. In the pretreatment tissues, more stromal CD3+FoxP3+ Tregs and CD86+/CD163+ macrophages were observed in patients with residual tumor existed in the resected lymph nodes (pN1), compared with pCR patients. Spatial analyses showed majority of macrophages were mainly distributed in close proximity to tumor nest in pN1 patients. In the posttreatment tissues, pCR patients had less CD86+ cells infiltration, whereas higher CD86+ cell densities were significantly associated with higher tumor regression grades (TRG) in non-pCR patients. When comparing the paired pre- and post-treatment samples, heterogeneous tumor-associated immune cell patterns were found. Upon to the treatment, CD3+ T lymphocytes were slightly increased in pCR patients, but markedly decreased in non-pCRs. In contrast, a noticeable increase and a less obvious decrease of CD86+ cell infiltration was depicted in non-pCRs and pCRs, respectively. Furthermore, opposite trends of the treatment-induced alterations of CD8+ and CD15+ cells were observed between pN0 and pN1 patients. Conclusions: Collectively, our data demonstrate a comprehensive picture of tumor immune landscape before and after neoadjuvant ICB combined with chemoradiotherapy, and therefore provide rationale for the further improvement of neoadjuvant therapy in ESCC.