Tumor microenvironment shows an immunological abscopal effect in patients with NSCLC treated with pembrolizumab-radiotherapy combination

Abstract

BackgroundImmunotherapy is currently part of the standard of care for patients with advanced-stage non-small cell lung cancer (NSCLC). However, many patients do not respond to this treatment, therefore combination strategies are being explored to increase clinical benefit. The PEMBRO-RT trial combined the therapeutic programmed cell death 1 (PD-1) antibody pembrolizumab with stereotactic body radiation therapy (SBRT) to increase the overall response rate and study the effects on the tumor microenvironment (TME).MethodsHere, immune infiltrates in the TME of patients included in the PEMBRO-RT trial were investigated. Tumor biopsies of patients treated with pembrolizumab alone or combined with SBRT (a biopsy of the non-irradiated site) at baseline and during treatment were stained with multiplex immunofluorescence for CD3, CD8, CD20, CD103 and FoxP3 for lymphocytes, pan-cytokeratin for tumors, and HLA-ABC expression was determined.ResultsThe total number of lymphocytes increased significantly after 6 weeks of treatment in the anti-PD-1 group (fold change: 1.87, 95% CI: 1.06 to 3.29) and the anti-PD-1+SBRT group (fold change: 2.29, 95% CI: 1.46 to 3.60). The combination of SBRT and anti-PD-1 induced a 4.87-fold increase (95% CI: 2.45 to 9.68) in CD103+cytotoxic T-cells 6 weeks on treatment and a 2.56-fold increase (95% CI: 1.03 to 6.36) after anti-PD-1 therapy alone. Responders had a significantly higher number of lymphocytes at baseline than non-responders (fold difference 1.85, 95% CI: 1.04 to 3.29 for anti-PD-1 and fold change 1.93, 95% CI: 1.08 to 3.44 for anti-PD-1+SBRT).ConclusionThis explorative study shows that that lymphocyte infiltration in general, instead of the infiltration of a specific lymphocyte subset, is associated with response to therapy in patients with NSCLC.Furthermore, anti-PD-1+SBRT combination therapy induces an immunological abscopal effect in the TME represented by a superior infiltration of cytotoxic T cells as compared with anti-PD-1 monotherapy.

Modulation of CD8+ T Cell Responses by Radiotherapy—Current Evidence and Rationale for Combination with Immune Checkpoint Inhibitors

“…Additionally, the expansion of neoantigen-specific CD8 + T cells among circulating CD8 + T cells was observed. Of note, pembrolizumab plus SBRT increased the infiltration of CD8 + T cells, as well as those expressing CD103, more prominently than pembrolizumab alone in patients with metastatic NSCLC [144], suggesting that effects of RT on tumor-specific CD8 + T cells may enhance the anti-tumor activity of ICIs.…”

Immunotherapy Combined with Radiation in Malignant Melanoma without BRAF Mutations Brain Metastases—Favorable Response after Immunotherapy Continued beyond Progression

“…Immunotherapy administered concomitantly with radiotherapy highlights the potential synergism of the two therapeutic methods [42][43][44][45][46][47][48].…”

Radiotherapy remodels the tumor microenvironment for enhancing immunotherapeutic sensitivity

“…In a clinical trial for advanced NSCLC, SBRT + pembrolizumab only benefited the PD-L1-negative subgroup [ 161 ]. Subsequent analysis revealed that responders had higher overall baseline lymphocyte infiltration levels (1.93-fold) [ 162 ]. High baseline tumor PD-L1 expression (≥1%), low PD-1 + CD8 + cell density in tumors and a low ratio of PD-L1 + /CD4 + T cells were identified as being associated with better OS [ 151 ].…”