Alteration in tumoural PD-L1 expression and stromal CD8-positive tumour-infiltrating lymphocytes after concurrent chemo-radiotherapy for non-small cell lung cancer

Yoneda, Kazue; Kuwata, Taiji; Kanayama, Masatoshi; Mori, Masataka; Kawanami, Toshinori; Yatera, Kazuhiro; Ohguri, Takayuki; Hisaoka, Masanori; Nakayama, Toshiyuki; Tanaka, Fumihiro

doi:10.1038/s41416-019-0541-3

Cited by 97 publications

(92 citation statements)

References 33 publications

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“…There is an increasing body of preclinical and clinical data regarding the radiotherapy‐induced immunomodulatory effects in the local tumor microenvironment, supporting the combination strategy . Radiotherapy modifies the tumor microenvironment, including enhanced antigen presentation, and the upregulation of tumor programmed death ligand‐1 and major histocompatibility complex class I expression . In addition to the local effects of irradiation at the tumor site, radiotherapy can also mediate an abscopal effect, which is linked to an immune‐mediated mechanism .…”

Section: Discussionmentioning

confidence: 99%

Current status and progress of concurrent chemoradiotherapy in patients with locally advanced non‐small cell lung cancer prior to the approval of durvalumab

et al. 2020

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Background: The standard treatment for patients with unresectable locally advanced (LA) non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT). Consolidation therapy with durvalumab after CRT demonstrated survival benefits and was approved in Japan in July 2018. The use of immune checkpoint inhibitors (ICIs) is entering routine oncological practice, and here we investigate the feasibility of concurrent CRT for LA-NSCLC patients based on the PACIFIC criteria. Methods: We performed a retrospective study to evaluate the feasibility and efficacy of concurrent CRT prior to the approval of durvalumab. We assessed consecutive patients with LA-NSCLC treated with CRT between January 2012 and June 2018. Results: We analyzed a total of 108 consecutive patients who received radical thoracic radiotherapy and concurrent platinum-based chemotherapy. Of those patients, 105 (97%) completed the planned radiotherapy. Radiation pneumonitis was observed in 93 patients (85%), with a median of 130 days (range: 41-317 days) from the initiation of radiation to the onset of the complication. Among the patients, 74 (69%) were considered eligible for consolidation therapy with durvalumab. The overall response rate was 64%, and the two-year survival rate was 63%. Patients who received an ICI after relapse were associated with significantly better survival than those who did not receive an ICI (two-year survival rate: 87% vs. 41%, respectively; P = 0.001). Conclusions: Prior to the approval of durvalumab, the clinical application of ICIs improved the outcome of patients with relapsed NSCLC after CRT for LA-NSCLC. The management of radiation pneumonitis remains a challenge following the approval of durvalumab.

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Section: Discussionmentioning

confidence: 99%

Current status and progress of concurrent chemoradiotherapy in patients with locally advanced non‐small cell lung cancer prior to the approval of durvalumab

et al. 2020

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“…Several reports demonstrate that PD-L1 expression is upregulated by RT or chemotherapy ( Lim et al, 2016 , 2017 ; Kelly et al, 2018 ; Yoneda et al, 2019 ). Recently, we reported that DSBs upregulate PD-L1 expression in a transcription-dependent manner via the STAT-IRF1 pathway ( Figure 2 ; Sato et al, 2017 ).…”

Section: Regulation Of Pd-l1 Expression In the Context Of Dna Damagementioning

confidence: 99%

DNA Repair and Signaling in Immune-Related Cancer Therapy

Kakoti

Sato

Laskar

et al. 2020

Front. Mol. Biosci.

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Cancer therapy using immune checkpoint inhibitors (ICIs) is a promising clinical strategy for patients with multiple types of cancer. The expression of programmed cell death ligand-1 (PD-L1), an immune-suppressor ligand, in cancer cells is a factor that influences the efficacy of ICI therapy, particularly in the anti-programmed cell death protein-1 (PD-1)/PD-L1 antibody therapy. PD-L1 expression in cancer cells are associated with tumor mutation burden including microsatellite instability because the accumulation of mutations in the cancer genome can produce abnormal proteins via mutant mRNAs, resulting in neoantigen production and HLA-neoantigen complex presentation in cancer cells. HLA-neoantigen presentation promotes immune activity within tumor environment; therefore, known as hot tumor. Thus, as the fidelity of DNA repair affects the generation of genomic mutations, the status of DNA repair and signaling in cancer cells can be considered prior to ICI therapy. The Cancer Genome Atlas (TCGA) and The Cancer Immunome Atlas (TCIA) database analysis showed that tumor samples harboring mutations in any non-homologous end joining, homologous recombination, or DNA damage signaling genes exhibit high neoantigen levels. Alternatively, an urgent task is to understand how the DNA damage-associated cancer treatments change the status of immune activity in patients because multiple clinical trials on combination therapy are ongoing. Recent studies demonstrated that multiple pathways regulate PD-L1 expression in cancer cells. Here, we summarize the regulation of the immune response to ICI therapy, including PD-L1 expression, and also discuss the potential strategies to improve the efficacy of ICI therapy for poor responders from the viewpoint of DNA damage response before or after DNA damage-associated cancer treatment.

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“…Previous studies have reported that chemoradiation can give rise to a number of immune reactions crucial to tumor containment. These include increased type I interferon and major histocompatibility complex (MHC) class I expression, as well as enhanced priming capacity of tumor‐infiltrating dendritic cells; all of which may contribute to the increased tumor infiltration of the effector CD8 T cells . Given that, the subsequent administration of the programmed cell death 1 (PD‐1) or PD‐1 ligand (PD‐L1) inhibitors, acting to mitigate the PD‐1/PD‐L1‐mediated immunosuppression, sustains the effector immunity established post‐chemoradiation around the tumor microenvironment and thereby contain the residual disease through an operational immune surveillance.…”

Section: Introductionmentioning

confidence: 99%

Consolidation treatment of durvalumab after chemoradiation in real‐world patients with stage III unresectable non‐small cell lung cancer

et al. 2020

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Background: Treatment for stage III non-small cell lung cancer (NSCLC) of unresectable disease mainly involves concurrent chemoradiation (CRT). Post-CRT consolidation treatment with durvalumab is a major therapeutic advance that provides survival benefit in this group of patients. However, the performance of this treatment strategy remains to be studied in a real-world setting. Methods: A total of 31 patients who had disease control post-CRT were included in the durvalumab early access program (EAP) as an intent-to-treat cohort and retrospectively reviewed for post-CRT progression-free survival (PFS) and time to metastatic disease or death (TMDD). The neutrophil-to-lymphocyte ratio (NLR) at the initiation of durvalumab was analyzed in 29 patients. Results: The median time from the completion of concurrent CRT to the initiation of durvalumb was 2.8 months. The objective response was 25.8% and the 12 month PFS and TMDD-free rate were 56.4% and 66.9%, respectively. The low NLR patients showed a significantly longer post-CRT PFS (not reach vs. 12.0 months [95% CI: 5.5-not estimable]; P = 0.040; the hazard ratio for disease progression or death, 0.23 [95% CI: 0.05-1.00]; P = 0.048) and the 12 month post-CRT PFS rate (82.5 vs. 42.6%). The post-CRT TMDD (not reach vs. 12.6 months, [95% CI: 10.8-not estimable]; P = 0.010; the hazard ratio for distant metastasis or death, 0.11 [95% CI: 0.01-0.88]; P = 0.037) and 12 month post-CRT TMDD-free rate (90.9 vs. 57.1%) were also significantly higher in the low NLR patients. Conclusions: Durvalumab consolidation treatment in real-world patients showed substantial efficacy and the correlation with the NLR level warrants further investigation.

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Alteration in tumoural PD-L1 expression and stromal CD8-positive tumour-infiltrating lymphocytes after concurrent chemo-radiotherapy for non-small cell lung cancer

Cited by 97 publications

References 33 publications

Current status and progress of concurrent chemoradiotherapy in patients with locally advanced non‐small cell lung cancer prior to the approval of durvalumab

Current status and progress of concurrent chemoradiotherapy in patients with locally advanced non‐small cell lung cancer prior to the approval of durvalumab

DNA Repair and Signaling in Immune-Related Cancer Therapy

Consolidation treatment of durvalumab after chemoradiation in real‐world patients with stage III unresectable non‐small cell lung cancer

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