A Long-term Response to Nivolumab in a Case of PD-L1-negative Lung Adenocarcinoma with an &lt;i&gt;EGFR&lt;/i&gt; Mutation and Surrounding PD-L1-positive Tumor-associated Macrophages

Watanabe, Hiromi; Ohashi, Kadoaki; Nishii, Kazuya; Seike, Keisuke; Makimoto, Go; Hotta, Katsuyuki; Maeda, Yoshinobu; Kiura, Katsuyuki

doi:10.2169/internalmedicine.2875-19

Cited by 10 publications

(14 citation statements)

References 23 publications

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“…The CD68-positive macrophages were also positive for CD163 (M2-like macrophage), a marker for immunosuppressive tumor-associated macrophages (TAMs). Considering the availability of similar reports in the past [ 26 ], the excellent therapeutic effects observed in our case can be attributed to the following scenarios: (1) TAMs suppressed CD8-positive lymphocytes, (2) nivolumab inhibited the negative interaction of M2 macrophages, and (3) CD8-positive lymphocytes were released and attacked the tumor. However, given that this is a case report, future case series are needed to validate such mechanisms.…”

Section: Discussionsupporting

confidence: 56%

Successful laparoscopic conversion surgery for gastric cancer with para-aortic lymph node metastasis after third-line chemotherapy: a case report

et al. 2021

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We herein reported a case of advanced gastric cancer (GC) with para-aortic lymph node (PALN) metastases who successful achieved downstaging following systemic chemotherapy and underwent curative laparoscopic conversion surgery. A 74-year-old male patient diagnosed with advanced GC and PALN metastases [cT4N3M1(LYM), stage IVA] was administered chemotherapy and immunotherapy for 28 months. After 27 courses of nivolumab as third-line chemotherapy, PALN enlargement was resolved, for which conversion surgery was planned. Subsequently, laparoscopic distal D2 gastrectomy with sampling para-aortic lymphadenectomy was performed, after which a pathological diagnosis of type V moderately differentiated tubular adenocarcinoma with mucinous adenocarcinoma, stage ypT3 (SS), ly1c, and v0, was established. The pathological proximal and distal tumor margins were negative. One lymph node metastasis was observed (No. 6; 1/25). The sampled lymph nodes were negative (No. 16a1: 0/2). The therapeutic effect was categorized as Grade 1a. The postoperative course was uneventful, with the patient receiving nivolumab to control for potential PALN metastases. Postoperatively, no recurrence was observed over 11 months. Laparoscopic conversion gastrectomy was successfully performed in a patient with advanced GC that was originally unresectable, suggesting that minimally invasive surgery may be a good option for originally unresectable advanced GC that becomes resectable.

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Section: Discussionsupporting

confidence: 56%

Successful laparoscopic conversion surgery for gastric cancer with para-aortic lymph node metastasis after third-line chemotherapy: a case report

et al. 2021

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“…Recent case report is available that suggested that TAMs in lung cancer can be a predictor of a positive response to anti-PD-1 antibodies (nivolumab) in patents with EGFR-mutated lung cancer (197). In this case report a 72-year old male patient with lung adenocarcinoma (cT1bN2M0, cStage IIIA) was harboring anEGFRexon19 deletion.…”

Section: Tams and Lung Cancer Treatmentmentioning

confidence: 87%

“…After seven cycles of nivolumab administration, the patient has continued treatment with nivolumab for more than two years with no evidence of tumor regrowth or serious immunerelated adverse events (197). TAMs were analyzed in lung tumor by IHC, and CD68, CD206 and PD-L1 expression was detected (197). However, this study does not provide any evidence for the dynamic changes of TAM amounts or phenotypes in primary tumor and metastatic sites and also during different chemotherapy approaches.…”

Section: Tams and Lung Cancer Treatmentmentioning

confidence: 91%

“…Although, the PD-L1 expression was negative, nivolumab was administered as sixthline therapy. After seven cycles of nivolumab administration, the patient has continued treatment with nivolumab for more than two years with no evidence of tumor regrowth or serious immunerelated adverse events (197). TAMs were analyzed in lung tumor by IHC, and CD68, CD206 and PD-L1 expression was detected (197).…”

Section: Tams and Lung Cancer Treatmentmentioning

confidence: 99%

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Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers

et al. 2020

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Tumor-associated macrophages (TAMs) are major innate immune cells that constitute up to 50% of the cell mass of human tumors. TAMs are highly heterogeneous cells that originate from resident tissue-specific macrophages and from newly recruited monocytes. TAMs' variability strongly depends on cancer type, stage, and intratumor heterogeneity. Majority of TAMs are programmed by tumor microenvironment to support primary tumor growth and metastatic spread. However, TAMs can also restrict tumor growth and metastasis. In this review, we summarized the knowledge about the role of TAMs in tumor growth, metastasis and in the response to cancer therapy in patients with five aggressive types of cancer: breast, colorectal, lung, ovarian, and prostate cancers that are frequently metastasize into distant organs resulting in high mortality of the patients. Two major TAM parameters are applied for the evaluation of TAM correlation with the cancer progression: total amount of TAMs and specific phenotype of TAMs identified by functional biomarkers. We summarized the data generated in the wide range of international patient cohorts on the correlation of TAMs with clinical and pathological parameters of tumor progression including lymphatic and hematogenous metastasis, recurrence, survival, therapy efficiency. We described currently available biomarkers for TAMs that can be measured in patients' samples (tumor tissue and blood). CD68 is the major biomarker for the quantification of total TAM amounts, while transmembrane receptors (stabilin-1, CD163, CD206, CD204, MARCO) and secreted chitinase-like proteins (YKL-39, YKL-40) are used as biomarkers for the functional TAM polarization. We also considered that specific role of TAMs in tumor progression can depend on the localization in the intratumoral compartments. We have made the conclusion for the role of TAMs in primary tumor growth, metastasis, and therapy sensitivity for breast, colorectal, lung, ovarian, and prostate cancers. In contrast to other cancer types, majority of clinical studies indicate that TAMs in colorectal cancer have protective role for the patient and interfere with primary tumor growth

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“…Previous studies reported about the potential indispensable role of PD-L1 expressed by non-tumor cells on PD-L1 blockade-mediated tumor elimination in murine tumor models and the correlation between PD-L1-positive macrophages and the positive effects of anti-PD-L1 and anti-PD-1 antibodies in lung cancers and melanoma. [45][46][47] Our study might offer a clue to select intratumor PD-L1positive macrophages as promising biomarker for the use of checkpoint inhibitors.…”

Section: Open Accessmentioning

confidence: 94%

Development and validation of the immune signature to predict distant metastasis in patients with nasopharyngeal carcinoma

Liu

Bian

Liu

et al. 2020

J Immunother Cancer

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BackgroundThe tumor immune microenvironment has clinicopathological significance in predicting prognosis and therapeutic efficacy. We aimed to develop an immune signature to predict distant metastasis in patients with nasopharyngeal carcinoma (NPC).MethodsUsing multiplexed quantitative fluorescence, we detected 17 immune biomarkers in a primary screening cohort of 54 NPC tissues presenting with/without distant metastasis following radical therapy. The LASSO (least absolute shrinkage and selection operator) logistic regression model used statistically significant survival markers in the training cohort (n=194) to build an immune signature. The prognostic and predictive accuracy of it was validated in an external independent group of 304 patients.ResultsEight statistically significant markers were identified in the screening cohort. The immune signature consisting of four immune markers (PD-L1+ CD163+, CXCR5, CD117) in intratumor was adopted to classify patients into high and low risk in the training cohort and it showed a high level of reproducibility between different batches of samples (r=0.988 for intratumor; p<0.0001). High-risk patients had shorter distant metastasis-free survival (HR 5.608, 95% CI 2.619 to 12.006; p<0.0001) and progression-free survival (HR 2.798, 95% CI 1.498 to 5.266; p=0·001). The C-indexes which reflected the predictive capacity in training and validation cohort were 0.703 and 0.636, respectively. Low-risk patients benefited from induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) (HR 0.355, 95% CI 0.147 to 0.857; p=0·021), while high-risk patients did not (HR 1.329, 95% CI 0.543 to 3.253; p=0·533). To predict the individual risk of distant metastasis, nomograms with the integration of both immune signature and clinicopathological risk factors were developed.ConclusionsThe immune signature provided a reliable estimate of distant metastasis risk in patients with NPC and might be applied to identify the cohort which benefit from IC+CCRT.

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A Long-term Response to Nivolumab in a Case of PD-L1-negative Lung Adenocarcinoma with an <i>EGFR</i> Mutation and Surrounding PD-L1-positive Tumor-associated Macrophages

Cited by 10 publications

References 23 publications

Successful laparoscopic conversion surgery for gastric cancer with para-aortic lymph node metastasis after third-line chemotherapy: a case report

Successful laparoscopic conversion surgery for gastric cancer with para-aortic lymph node metastasis after third-line chemotherapy: a case report

Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers

Development and validation of the immune signature to predict distant metastasis in patients with nasopharyngeal carcinoma

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