Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination

Yu, Jiali; Green, Michael D.; Li, Shasha; Sun, Yilun; Journey, Sara N.; Choi, Jae Eun; Rizvi, Syed Monem; Qin, Angel; Waninger, Jessica; Lang, Xueting; Chopra, Zoey; Naqa, Issam El; Zhang, Jiajia; Bian, Yingjie; Jiang, Long; Tezel, Alangoya; Skvarce, Jeremy; Achar, Rohan K.; Sitto, Merna; Rosen, Benjamin; Su, Fengyun; Narayanan, Sathiya Pandi; Cao, Xuhong; Wei, Shuang; Szeliga, Wojciech; Vatan, Linda; Mayo, Charles S.; Morgan, Meredith A.; Schonewolf, Caitlin; Cuneo, Kyle C.; Kryczek, Ilona; Vincent, Tiffaney L.; Lao, Christopher D.; Lawrence, Theodore S.; Ramnath, Nithya; Wen, Fei; Chinnaiyan, Arul M.; Cieślik, Marcin; Alva, Ajjai; Zou, Weiping

doi:10.1038/s41591-020-1131-x

Cited by 565 publications

(541 citation statements)

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“…Yu et al reported that liverdirected radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival, and reduces hepatic siphoning of T cells. The combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity (28). Furthermore, palliative liver-directed radiotherapy resulted in a clinically meaningful improvement in symptoms for advanced HCC patients with pain or abdominal discomfort and has tolerable toxicity (29,30).…”

Section: Discussionmentioning

confidence: 99%

Safety of PD-1/PD-L1 Inhibitors Combined With Palliative Radiotherapy and Anti-Angiogenic Therapy in Advanced Hepatocellular Carcinoma

Zhong

Peng

et al. 2021

Front. Oncol.

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BackgroundPrevious studies have explored cancer immunotherapy with radiotherapy or anti-angiogenic therapy, but no trials have reported a triple therapy approach. This study aimed to investigate safety and clinical outcome of PD-1/PD-L1 inhibitors combined with palliative radiotherapy and targeted angiogenesis therapy in hepatocellular carcinoma (HCC) of Barcelona Clinic Liver Cancer (BCLC) stage C.MethodsConsecutive patients (n=16) treated with PD-1/PD-L1 inhibitors combined with radiotherapy and anti-angiogenic therapy in a bi-institutional cohort between July 2017 and December 2020 were retrospectively included. Radiotherapy was conducted within 14 days of the first administration of immunotherapy. The primary endpoint was treatment-related adverse event (TRAE).ResultsThe median follow-up was 383 days. Fifteen patients (93.8%) experienced at least 1 TRAE. The most common TRAEs of any grade were rash (25%), diarrhea (25%), aspartate aminotransferase increase (18.8%), alanine transaminase increase (18.8%), decreased appetite (18.8%), and fatigue (18.8%). Grade 3/4 TRAEs occurred in 4 patients (25%) and finally led to treatment interruption. No patient death was attributed to treatment. No specific events were responsible for the addition of radiotherapy. Six patients showed partial response, 7 showed stable disease, and 2 showed progressive disease. The objective response rate and disease control rate were 40.0% (95% CI 16.3%–67.7%) and 86.7% (95% CI 59.5%–98.3%), respectively. Moreover, the median progression-free survival was 140 days. Patients had a median overall survival of 637 days, and the estimated rates of survival at 6 and 12 months were 92.3% and 75.5%, respectively.ConclusionPD-1/PD-L1 inhibitors combined with palliative radiotherapy and anti-angiogenic therapy appear to be safe, with no unexpected adverse events. Additional studies exploring the clinical benefit are warranted.

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Section: Discussionmentioning

confidence: 99%

Safety of PD-1/PD-L1 Inhibitors Combined With Palliative Radiotherapy and Anti-Angiogenic Therapy in Advanced Hepatocellular Carcinoma

Zhong

Peng

et al. 2021

Front. Oncol.

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“…The general importance of T cell mediated anti-tumor effects has also been confirmed by an increasing number of CAR T approaches in HCC, usually targeting glypican 3 or AFP [65]. A recent report also demonstrated that hepatic FasL + CD11b + F4/80 + monocytederived macrophages can siphon activated CD8 + T cells and contribute to limited efficacy of immunotherapy [66]. In this section we will therefore expand the view also to myeloid cells like macrophages NK cells as well as the above-mentioned T cell checkpoints TIM-3, LAG-3 and TIGIT which have not yet been targeted in HCC.…”

Section: Future Options Of Hcc Linked Immunmodulationmentioning

confidence: 89%

Immunmodulatory Treatment Strategies of Hepatocellular Carcinoma: From Checkpoint Inhibitors Now to an Integrated Approach in the Future

Ocker

Mayr

Kiesslich

et al. 2021

Cancers

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Background: Hepatocellular carcinoma (HCC) still represents a human tumor entity with very limited therapeutic options, especially for advanced stages. Here, immune checkpoint modulating drugs alone or in combination with local ablative techniques could open a new and attractive therapeutic “door” to improve outcome and response rate for patients with HCC. Methods: Published data on HCC experimental to pre-(clinical) treatment strategies from standard of care to novel immunomodulatory concepts were summarized and discussed in detail. Results: Overall, our knowledge of the role of immune checkpoints in HCC is dramatically increased in the last years. Experimental and pre-clinical findings could be translated to phase 1 and 2 clinical trials and became standard of care. Local ablative techniques of HCC could improve the effectivity of immune checkpoint inhibitors in situ. Conclusions: This review demonstrates the importance of immunomodulatory treatment strategies of HCC, whereby the “best treatment code” of immune checkpoint drugs, combination with ablative techniques and of timing must be evaluated in coming clinical trials.

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“…Previous works have suggested that different anatomic locations of metastasis may correlate with tumour immunology. Especially liver metastasis has been linked to poor immunological tumour pro les and responses to immune checkpoint inhibitor treatments [13,16]. Tumour immunology has a central role in the prognosis of HER2 positive breast cancer and the cornerstone of its treatment are the HER2 targeted antibodies which effect signi cantly through immune activation [6,17].…”

Section: Discussionmentioning

confidence: 99%

“…Our ndings may suggest that the e cacy of HER2 antibody treatment might differ according to the metastatic site. Since liver metastasis are thought to induce general immunosuppression [13,16] and HER2 antibodies mediate their effects through antibody-dependent cellular cytotoxicity (ADCC)[6, 17], immunosuppression might be account for the results. Importantly, however our study includes quite recent patients and the treatment paradigms of HER2 positive breast cancer have been evolving in the last years with introduction of new HER2 antibodies and antibody-linked cytotoxic payloads and older studies might not capture the effects of these treatments.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study by Yu et al [13] showed that liver metastasis can affect systemic anti-tumoural immunity by recruiting immunosuppressive macrophages into liver, which leads to deletion of cytotoxic T-cells and diminish the e cacy of immune checkpoint inhibitors. Our previous studies with metastatic HER2 positive breast cancer have demonstrated a strong association of cytotoxic T-cells and M1-like macrophages in primary tumours with better prognosis [14,15].…”

Section: Introductionmentioning

confidence: 99%

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Immune Cell Profiles of Metastatic HER2 Positive Breast Cancer Patients According To The Sites of Metastasis

Honkanen

Luukkainen

Tikkanen

et al. 2021

Preprint

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Purpose: Recent works have characterized that metastatic site can affect the tumour immune profiles and efficiency of cancer immunotherapies. The prognosis of HER2 positive breast cancer is associated with the characteristics of the tumour immune microenvironment, with immunological cells playing a central role in efficiency of HER2 targeted antibodies. Here we investigated the prognostic significance of different metastatic sites and their correlation to tumour immune profiles in HER2 positive breast cancer treated with trastuzumab. Methods: We collected all (n=54) HER2 positive metastatic breast cancer patients treated with trastuzumab containing regimens at Oulu University Hospital 2009-2014. Pathological and clinical data were collected from electronic patient records. The tumour immune profiles were analysed from pre-treatment primary tumours using well-characterized immunological markers with computer-assisted immune cell counting. Results: Of the metastatic sites, only liver metastases were associated with poor prognosis (hazard ratio 1.809, 95% confidence interval 1.004 – 3.262), especially when presenting as the primary site of metastases. Of the other sites, pulmonary metastases characterized a patient profile with trend to improved survival. Of the studied tumour immunological markers, liver metastases had low densities of CD3+ T-cells (p=0.030) and M1-like macrophages in their primary tumours (p=0.025). Of the other studied markers and sites, pulmonary metastases had low STAB1+ immunosuppressive macrophage density in their primary tumours.Conclusions: Our results suggest that the site of metastasis is associated with prognosis in HER2 positive breast cancer, highlighted by the poor prognosis of liver metastases. Furthermore, liver metastases were associated with adverse tumour immune cell profiles.

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Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination

Cited by 565 publications

References 65 publications

Safety of PD-1/PD-L1 Inhibitors Combined With Palliative Radiotherapy and Anti-Angiogenic Therapy in Advanced Hepatocellular Carcinoma

Safety of PD-1/PD-L1 Inhibitors Combined With Palliative Radiotherapy and Anti-Angiogenic Therapy in Advanced Hepatocellular Carcinoma

Immunmodulatory Treatment Strategies of Hepatocellular Carcinoma: From Checkpoint Inhibitors Now to an Integrated Approach in the Future

Immune Cell Profiles of Metastatic HER2 Positive Breast Cancer Patients According To The Sites of Metastasis

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