A T cell-inflamed tumor microenvironment is characterized by the accumulation and local activation of CD8+ T cells and Bat3-lineage dendritic cells, which together are associated with clinical ...response to anti-programmed cell death protein 1 (anti-PD-1)-based immunotherapy. Preclinical models have demonstrated a crucial role for the chemokine CXCL10 in the recruitment of effector CD8+ T cells into the tumor site, and a chemokine gene signature is also seen in T cell-inflamed tumors from patients. However, the cellular source of CXCL10 in human solid tumors is not known. To identify the cellular source of CXCL10 we analyzed 22 pretreatment biopsy samples of melanoma metastases from patients who subsequently underwent checkpoint blockade immunotherapy. We stained for CD45+ and Sox10+ cells with multiparameter immunofluorescence staining, and RNA in situ hybridization technology was used in concert to identify CXCL10 transcripts. The results were correlated with the expression levels of CXCL10 transcripts from bulk RNA sequencing and the best overall response to immune checkpoint inhibition (anti-PD-1 alone or with anti-CTLA-4) in the same patients. We identified CD45+ cells as the major cellular source for CXCL10 in human melanoma metastases, with additional CXCL10 production seen by Sox10+ cells. Up to 90% of CD45+ cells and up to 69% of Sox10+ cells produced CXCL10 transcripts. The CXCL10 staining result was consistent with the level of CXCL10 expression determined by bulk RNA sequencing. The percentages of CD45+ CXCL10+ cells and Sox10+ CXCL10+ cells independently predicted response (p<0.001). The average number of transcripts per cell correlated with the CD45+ cell infiltrate (R=0.37). Immune cells and melanoma cells produce CXCL10 in human melanoma metastases. Intratumoral CXCL10 is a positive prognostic factor for response to immunotherapy, and the RNAscope technique is achievable using paraffin tissue. Strategies that support effector T cell recruitment via induction of CXCL10 should be considered as a mechanism-based intervention to expand immunotherapy efficacy.
Tumor regression grade of the primary tumor (TRG‐PT) and residual lymph node metastasis have been pathologically determined in esophageal squamous cell carcinoma (ESCC) patients who had received ...neoadjuvant chemotherapy (nCT) followed by surgery; however, TRG of the metastatic tumor involving lymph nodes (LN) has not yet been determined. The aim of the present study was to clarify the impact of TRG on the prognosis of ESCC patients. ESCC patients (n = 110) who had received nCT followed by surgery were enrolled. Dissected LN were classified into 2 categories: plausible positive metastatic LN (pp‐MLN) where viable and/or degenerated ESCC cells and/or tissue modifications were observed, and non‐metastatic LN (non‐MLN) where neither of them was observed. We defined nCT‐effective rate (CER) as the ratio of the number of pp‐MLN that showed tumor regression to the total number of pp‐MLN, and divided CER into low‐CER (LCER; ≥0% and <50%) and high‐CER (HCER; ≥50% and ≤100%). Relationships between CER and clinicopathological factors including prognosis were then examined. Multivariate analyses of 110 patients indicated that ypT3‐4 (P = .023, HR; 2.551), positive venous infiltration (P = .006, HR; 3.526), and LCER (P = .033, HR; 1.922) were independently associated with shorter recurrence‐free survival (RFS). Multivariate analyses of 43 patients with grade 0 TRG‐PT showed that ypT3‐4 (P = .033, HR; 3.397) and LCER (P = .008, HR; 3.543) were independently associated with shorter RFS. This study showed that CER was one of the prognostic factors for ESCC patients who had received nCT followed by surgery.
Tumor regression grade in lymph nodes was associated with the prognoses of esophageal squamous cell carcinoma (ESCC) patients after neoadjuvant chemotherapy (nCT). This important study shows a new predictor for ESCC patients after nCT.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Tumour microenvironments can differ according to intratumoural locations. We investigated the immune status at different locations in primary tumours and its clinical significance in oesophageal ...squamous cell carcinoma (ESCC).
The number of CD8
tumour-infiltrating immune cells (TIICs) and PD-1
TIICs, and PD-L1 expression on tumour cells (PD-L1
) were immunohistochemically examined in the surface (Surf), centre (Cent) and invasive front (Inv) of tumours surgically resected from 192 patients with ESCC.
The PD-L1
rate was lower in Inv than in Cent (12.0% vs. 18.2%, P = 0.012), although the numbers of CD8
TIICs and PD-1
TIICs were comparable among intratumoural locations. High numbers of CD8
and PD-1
TIICs and positive PD-L1
were related to better overall survival (OS) only in Surf and Cent (CD8: P = 0.012 in Surf, 0.018 in Cent, and 0.165 in Inv; PD-1: P = 0.028 in Surf, 0.021 in Cent, and 0.208 in Inv; and PD-L1: 0.044 in Surf, 0.026 in Cent, and 0.718 in Inv). Positive PD-L1
in Surf and/or Cent but not in Inv demonstrated a strong tendency toward better OS (P = 0.053).
Immune microenvironments according to the intratumoural location have different effects on the survival of patients with ESCC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Immunotherapy with anti-PD-1 antibody preliminarily showed promising efficacy for treating esophageal squamous cell carcinoma (ESCC). Herein, we used tissue microarrays and immunohistochemically ...analyzed PD-L1 and various tumor infiltrating immune cells (TIICs) in specimens from 196 ESCC patients who had undergone curative resection without preoperative therapy. PD-L1 expressions in tumor cells (TCs) and TIICs, as well as infiltration of lymphocytes (CD4+, CD8+, FOXP3+, and PD- 1+) and macrophages (CD68+ and CD204+), were evaluated. PD-L1 was expressed in TCs of 18.4% and in TIICs of 83.3% of these patients. PD-L1 expressions in TCs and TIICs were associated with significant infiltration of various TIIC types, especially CD8+ cells. PD-L1 expressions in both TCs and TIICs were significantly associated with favorable overall survival, and combining their levels enhanced prognostic accuracy. Prognostic impacts of PD-L1 expressions in TCs and TIICs, abundant PD-1+ cell infiltration, a high CD8+/FOXP3+ ratio, and the CD8+/CD204+ ratio remained significant after adjusting for clinicopathological factors. In conclusion, PD-L1 expression reflects anti-tumor immunity, and PD-1/PD-L1 expression and the ratio of infiltrating effector to immune suppressor cells have prognostic value. Therapeutic strategies inhibiting the PD-1/PD-L1 signal and immune suppressor cells are anticipated in ESCC patients.
Background and Aims Photodynamic therapy (PDT) is a less-invasive salvage treatment option for local failure at the primary site after chemoradiotherapy (CRT) for esophageal squamous cell carcinoma. ...The objective of this study was to clarify the long-term outcomes and prognostic factors of salvage PDT. Methods One hundred thirteen consecutive patients treated in our institution with PDT for local failure limited to within T2 without any metastases after definitive CRT performed between 1998 and 2008 were retrospectively enrolled. The complete response rate, adverse events, and survival outcomes were assessed and prognostic factors were investigated using a multivariate analysis. Results The complete response rate was 58.4% (95% confidence interval CI, 49.3%-67.5%). The progression-free survival (PFS) and the overall survival (OS) rates at 5 years after salvage PDT were 22.1% (95% CI, 14.3%-30.0%) and 35.9% (95% CI, 26.7%-45.1%). N0 before CRT was significantly associated with OS (hazard ratio HR, 0.54; 95% CI, 0.33-0.91, P = .020), whereas the impact of T1 or T2 before CRT on PFS (HR, 0.63; 95% CI, 0.38-1.04, P = .068) and that of a longer period between CRT and PDT on OS (HR, 0.64; 95% CI, 0.39-1.05, P = .078) were marginal. The treatment-related death rate was 1.8%. Conclusions Salvage PDT was found to have a superior outcome and a satisfactory safety profile. An earlier clinical stage before CRT and a longer interval between CRT and PDT may be associated with a longer survival period.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Backgrounds
Local recurrence after definitive chemoradiotherapy, if diagnosed early, can be cured by salvage endoscopic therapy, which allows organ preservation and contributes to maintaining patient ...quality of life. This study aimed to investigate early endoscopic findings of local recurrence in post-definitive chemoradiotherapy patients.
Methods
Between January 2008 and June 2012, 17 esophageal squamous cell carcinoma patients with no metastasis but local recurrence after definitive chemoradiotherapy were enrolled. We attempted to find endoscopic hallmarks suggestive of local recurrence by comparing pre- and post-local recurrence diagnostic images. The influence of follow-up schedule on chosen salvage therapy type was also investigated.
Results
Endoscopic local recurrence findings included eight submucosal tumors, five ulcers, and four erosions. Upon review of prior images, findings suggestive of local recurrence were detected in seven patients, including six submucosal tumors and one erosion, all of which were smaller than 10 mm. These lesions had changed morphologically at local recurrence diagnosis: three submucosal tumors had become larger and three submucosal tumors and one erosion had changed to ulcers. Of 12 patients with cT1 at local recurrence, four (33%) underwent follow-up endoscopy within 1 month of local recurrence findings and 11 patients (92%) were treated with salvage endoscopic therapy.
Conclusions
Endoscopists should be aware that SMTs or erosions, even those smaller than 10 mm, can indicate local recurrence after complete response to definitive chemoradiotherapy. Follow-up endoscopy should be performed within 1–2 months if findings suggestive of local recurrence are observed on prior endoscopy, even when biopsy results are negative.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The cellular source of positive signals that reinvigorate T cells within the tumor microenvironment (TME) for the therapeutic efficacy of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) ...blockade has not been clearly defined. We now show that Batf3-lineage dendritic cells (DCs) are essential in this process. Flow cytometric analysis, gene-targeted mice, and blocking antibody studies revealed that 4-1BBL is a major positive co-stimulatory signal provided by these DCs within the TME that translates to CD8+ T cell functional reinvigoration and tumor regression. Immunofluorescence and spatial transcriptomics on human tumor samples revealed clustering of Batf3+ DCs and CD8+ T cells, which correlates with anti-PD-1 efficacy. In addition, proximity to Batf3+ DCs within the TME is associated with CD8+ T cell transcriptional states linked to anti-PD-1 response. Our results demonstrate that Batf3+ DCs within the TME are critical for PD-1/PD-L1 blockade efficacy and indicate a major role for the 4-1BB/4-1BB ligand (4-1BBL) axis during this process.
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•DC1s are needed in the TME for PD-1/PD-L1 blockade efficacy•Anti-PD-L1-induced CD8+ T cell reinvigoration in the TME is 4-1BB/4-1BBL dependent•DC1/CD8+ T cell clustering is associated with clinical response to PD-1 blockade•CD8+ T cell proximity to DC1 is associated with transcriptomics linked to treatment response
Ziblat et al. demonstrate that Batf3+ dendritic cells (DC1s) are needed within the tumor for efficacy of PD-1/PD-L1 blockade. Mechanistically, they show that DC1s deliver positive signals through 4-1BB/4-1BBL for the reinvigoration of CD8+ T cells once PD-1/PD-L1 is blocked and that DC1-CD8 clustering correlates with anti-PD-1 clinical efficacy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose
The aim of the present study was to evaluate the incidence and explore the risk factors of febrile neutropenia (FN) in patients with esophageal cancer receiving neoadjuvant docetaxel, ...cisplatin, and 5-fluorouracil (DCF) chemotherapy in real-world settings.
Methods
We retrospectively reviewed clinical data of 128 consecutive patients with esophageal cancer. Specifically, these patients underwent neoadjuvant DCF chemotherapy with prophylactic antibiotic administration at our institution between July 2009 and January 2015. Two FN-related endpoints were set as follows: definite FN (dFN) defined as grade 4 neutropenia at the onset of fever and clinically suspected FN (csFN), which included both patients with dFN and patients without grade 4 neutropenia but with deteriorating grade 3 neutropenia at the onset of fever who were clinically diagnosed with FN for which they underwent treatment. The risk factors for dFN and csFN were evaluated based on patients’ characteristics.
Results
A total of 72 (56.3%) patients developed grade 3 or grade 4 neutropenia and 26 (20.3%) developed csFN including 14 (10.9%) with dFN. Multivariate analysis revealed that older age (OR 3.57, CI 1.27–10.1,
P
= 0.016) and living alone (OR 5.17, 95% CI 1.26–21.3,
P
= 0.023) were statistically significant risk factors for csFN development. As to dFN, no statistically significant risk factors were identified.
Conclusions
Older age and living alone are significant risk factors for developing FN, and thus, particularly for patients with risk factors for FN, G-CSF should be considered instead of prophylactic antibiotics with careful observation.
Clinically localized renal cell carcinoma is treated primarily with surgery followed by observation or adjuvant sunitinib in selected high-risk patients. The checkpoint inhibitor immunotherapeutic ...agents nivolumab and ipilimumab have recently shown a survival benefit in the first-line metastatic setting. To date, there have been no reports on the response of localized renal cancer to modern immunotherapy. We report a remarkable response of an advanced tumor thrombus to combined immunotherapy which facilitated curative-intent resection of the non-responding primary renal tumor. We characterized the tumor microenvironment within the responding and non-responding tumors.
A 54-year-old female was diagnosed with a locally advanced clear cell renal cell carcinoma with a level IV tumor thrombus of the vena cava. She was initially deemed unfit for surgical resection due to poor performance status. She underwent neoadjuvant immunotherapy with nivolumab and ipilimumab with a complete response of the vena cava and renal vein tumor thrombus, but had stable disease within her renal mass. She underwent complete surgical resection with negative margins and remains disease-free longer than 1 year after her diagnosis with no further systemic therapy. Notably, pathologic analysis showed a complete response within the vena cava and renal vein, but substantial viable cancer remained in the kidney. Multichannel immunofluorescence was performed and showed marked infiltration of immune cells including CD8
T cells and Batf3
dendritic cells in the thrombus, while the residual renal tumor showed a non-T cell-inflamed phenotype.
Preoperative immunotherapy with nivolumab and ipilimumab for locally advanced clear cell renal cancer resulted in a complete response of an extensive vena cava tumor thrombus, which enabled curative-intent resection of a non-responding primary tumor. If validated in larger cohorts, preoperative immunotherapy for locally advanced renal cell carcinoma may ultimately impact surgical planning and long-term prognosis.
BackgroundA T cell-rich tumor microenvironment has been associated with improved clinical outcome and response to immune checkpoint blockade therapies in several adult cancers. Understanding the ...mechanisms for lack of immune cell infiltration is critical for expanding immunotherapy efficacy in the clinic. To gain new insights into the mechanisms of poor tumor immunogenicity, we turned to pediatric cancers, which are generally unresponsive to checkpoint blockade.MethodsRNAseq and clinical data were obtained for Wilms tumor, rhabdoid tumor, osteosarcoma, and neuroblastoma from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database, and adult cancers from TCGA. Using an 18-gene tumor inflammation signature (TIS) representing activated CD8+ T cells, we identified genes significantly anti-correlated with the signature. Immunofluorescence was performed on metastatic melanoma samples for CD8, MSH2, and the tumor cell marker SOX10, and analyzed for relationship to anti-PD-1 efficacy.ResultsAmong the four pediatric cancers, we observed the lowest TIS scores in Wilms tumor. Wilms tumors demonstrated significantly lower T cell inflammation signatures than matched normal kidney samples, other pediatric tumor samples, and adult kidney tumor samples. Pathway analysis identified multiple types of DNA repair were upregulated in Wilms tumor and a score generated from the top 50 DNA repair genes strongly anti-correlated with TIS. This striking negative association was also observed in most adult tumor types. The anti-correlation was found to be independent of tumor mutation burden, suggesting that high expression of DNA repair pathway machinery may restrict tumor immunogenicity by mechanisms beyond prevention neoantigen accumulation. MSH2 was one of the top DNA repair genes identified from the Wilms tumor analysis and was confirmed to have a strong anti-correlation with TIS in melanoma samples from TCGA. Immunofluorescence from an independent cohort of metastatic melanoma patients revealed a significant negative correlation between CD8+ T cell numbers and MSH2+ SOX10+ tumor cell numbers. Additionally, non-responders to anti-PD-1 immunotherapy had significantly higher numbers of MSH2+ SOX10+ tumor cells than responders.ConclusionsIncreased tumor expression of DNA repair genes is associated with a less robust immune response in Wilms tumor, and this was also observed in the majority of TCGA tumor types. Surprisingly, the negative relationship between DNA repair score and TIS remained strong across TCGA when correcting for mutation count, indicating a potential role for DNA repair genes outside of preventing the accumulation of mutations. Strategies targeting DNA repair pathways could be considered as new therapeutic interventions to transform non-T cell-inflamed tumors into immune-responsive tumors.Ethics ApprovalThe study obtained ethics approval under IRB protocol 15-0837.
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