Chemotherapy but Not the Tumor Draining Lymph Nodes Determine the Immunotherapy Response in Secondary Tumors

Zhao, Xianda; Kassaye, Beminet; Wangmo, Dechen; Lou, Emil; Subramanian, Subbaya

doi:10.1016/j.isci.2020.101056

Cited by 21 publications

(22 citation statements)

References 52 publications

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“…To our knowledge, this is the first article reporting the effect of prior neck dissection on immunotherapy in humans. The results observed in our study are consistent with recent preclinical data [ 20 ]. A plausible reason why neck dissection did not affect the effectiveness of nivolumab in this study could be the contribution of other lymph nodes to lymphocyte migration toward the tumor site when regional lymph nodes were dissected in humans [ 21 ].…”

Section: Discussionsupporting

confidence: 94%

“…It has been shown in mouse models that lymph node dissection reduces the effect of immunotherapy involving PD-1 and PD-L1 inhibitory antibodies [ 17 ]. In contrast, a recent study using mouse models has shown that lymph node dissection alongside established primary tumors did not affect response to immune checkpoint blockades for artificially recurrent tumors owing to the distribution of tumor-specific T cells from peripheral lymphatic organs [ 20 ]. To our knowledge, this is the first article reporting the effect of prior neck dissection on immunotherapy in humans.…”

Section: Discussionmentioning

confidence: 99%

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Effectiveness of nivolumab affected by prior cetuximab use and neck dissection in Japanese patients with recurrent or metastatic head and neck cancer: results from a retrospective observational study in a real-world setting

et al. 2021

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Background To examine the effect of prior use of cetuximab and neck dissection on the effectiveness of nivolumab, we conducted a large-scale subgroup analysis in Japanese patients with recurrent/metastatic head and neck cancer. Methods Data on the effectiveness of nivolumab were extracted from patient medical records. All patients were analyzed for effectiveness by prior cetuximab use. In the analyses for prior neck dissection, only patients with locally advanced disease were included. Results Of 256 patients analyzed, 155 had received prior cetuximab. Nineteen of 50 patients with local recurrence underwent neck dissection. The objective response rate was 14.7 vs 17.2% (p = 0.6116), median progression-free survival was 2.0 vs 3.1 months (p = 0.0261), and median overall survival was 8.4 vs 12 months (p = 0.0548) with vs without prior cetuximab use, respectively. The objective response rate was 23.1 vs 25.9% (p = 0.8455), median progression-free survival was 1.8 vs 3.0 months (p = 0.6650), and median overall survival was 9.1 vs 9.9 months (p = 0.5289) with vs without neck dissection, respectively. Conclusions These findings support the use of nivolumab for patients with recurrent/metastatic head and neck cancer regardless of prior cetuximab use or neck dissection history. Trial registration number UMIN-CTR (UMIN000032600), Clinicaltrials.gov (NCT03569436)

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Effectiveness of nivolumab affected by prior cetuximab use and neck dissection in Japanese patients with recurrent or metastatic head and neck cancer: results from a retrospective observational study in a real-world setting

et al. 2021

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“…Consequently, the intensity of anti-tumor immunity and response to ICB is significantly restricted by ACKR4 loss. These data echos our previous work showing that the immune response that happens in TdLNs is extremely critical for initiating anti-tumor immunity[27]. In addition, our study also indicates that miR-552 negatively regulates ACKR4, and blocking the function of miR-552 increases ACKR4 expression in human CRC cell lines.…”

Section: Discussionsupporting

confidence: 89%

Loss of ACKR4 in tumor cells dysregulates dendritic cell migration to tumor-draining lymph nodes and T-cell priming

Wangmo

Premsrirut²,

Yuan

et al. 2021

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Colorectal cancer (CRC) is one of the most common malignancies in both morbidity and mortality. Immune checkpoint blockade (ICB) treatments have been successful in a portion of mismatch repair-deficient (dMMR) CRC patients but failed in the mismatch repair-proficient (pMMR) CRC patients. Atypical Chemokine Receptor 4 (ACKR4) is known for regulating dendritic cell (DC) migration. However, the roles of ACKR4 in CRC development and immunoregulation are unclear. By analyzing human CRC tissues, transgenic animals, and genetically modified CRC cells lines, our study revealed an important function of ACKR4 in maintaining CRC immune response. Loss of ACKR4 in CRC is associated with poor immune infiltration in the tumor microenvironment. More importantly, loss of ACKR4 in CRC tumor cells, rather than stromal cells, restrains the DC migration and antigen presentation to the tumor-draining lymph nodes (TdLNs). Tumors with ACKR4 knockdown become less sensitive to immune checkpoint blockades. Finally, we identified that microRNA-552 negatively regulates ACKR4 expression in human CRC. Taken together, our work identifies a critical mechanism for the maintenance of the DC-mediated T-cell priming in the TdLNs. These new findings demonstrate a novel mechanism leading to immunosuppression and ICB treatment resistance in CRC tumors.

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“…However, both our findings and the current literature suggest that this information may be of value. This would be especially interesting in the light of regional (tumor-draining) lymph nodes which play a critical role in terms of anti-tumor immunity and priming ( 36 ), increased expression of cytokines and checkpoint markers ( 37 ), and changes in the immune compartments resulting in a tumor favorable microenvironment ( 38 ). A major hurdle that remains in the analysis of lymph nodes is represented by the radiological assessment, often in contrast with the pathological one.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of Deep Learning-Mediated Treatment Monitoring in Lung Cancer Patients Receiving Immunotherapy

et al. 2021

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BackgroundCheckpoint inhibitors provided sustained clinical benefit to metastatic lung cancer patients. Nonetheless, prognostic markers in metastatic settings are still under research. Imaging offers distinctive advantages, providing whole-body information non-invasively, while routinely available in most clinics. We hypothesized that more prognostic information can be extracted by employing artificial intelligence (AI) for treatment monitoring, superior to 2D tumor growth criteria.MethodsA cohort of 152 stage-IV non-small-cell lung cancer patients (NSCLC) (73 discovery, 79 test, 903CTs), who received nivolumab were retrospectively collected. We trained a neural network to identify morphological changes on chest CT acquired during patients’ follow-ups. A classifier was employed to link imaging features learned by the network with overall survival.ResultsOur results showed significant performance in the independent test set to predict 1-year overall survival from the date of image acquisition, with an average area under the curve (AUC) of 0.69 (p < 0.01), up to AUC 0.75 (p < 0.01) in the first 3 to 5 months of treatment, and 0.67 AUC (p = 0.01) for durable clinical benefit (6 months progression-free survival). We found the AI-derived survival score to be independent of clinical, radiological, PDL1, and histopathological factors. Visual analysis of AI-generated prognostic heatmaps revealed relative prognostic importance of morphological nodal changes in the mediastinum, supraclavicular, and hilar regions, lung and bone metastases, as well as pleural effusions, atelectasis, and consolidations.ConclusionsOur results demonstrate that deep learning can quantify tumor- and non–tumor-related morphological changes important for prognostication on serial imaging. Further investigation should focus on the implementation of this technique beyond thoracic imaging.

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Chemotherapy but Not the Tumor Draining Lymph Nodes Determine the Immunotherapy Response in Secondary Tumors

Cited by 21 publications

References 52 publications

Effectiveness of nivolumab affected by prior cetuximab use and neck dissection in Japanese patients with recurrent or metastatic head and neck cancer: results from a retrospective observational study in a real-world setting

Effectiveness of nivolumab affected by prior cetuximab use and neck dissection in Japanese patients with recurrent or metastatic head and neck cancer: results from a retrospective observational study in a real-world setting

Loss of ACKR4 in tumor cells dysregulates dendritic cell migration to tumor-draining lymph nodes and T-cell priming

Prognostic Value of Deep Learning-Mediated Treatment Monitoring in Lung Cancer Patients Receiving Immunotherapy

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