Rethinking immune checkpoint blockade: ‘Beyond the T cell’

Liu, Xiuting; Hogg, Graham D.; DeNardo, David G.

doi:10.1136/jitc-2020-001460

Cited by 99 publications

(84 citation statements)

References 96 publications

(155 reference statements)

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“…CTLA-4 or PD-L1 blockade downregulated the frequency of immune cells in TC-1induced tumors, while anti-CTLA-4 treatment upregulated the frequency of most lymphoid cells in TC-1/dCD80-1-induced tumors. Enhanced infiltration of immune cells into tumors treated with immune checkpoint inhibitors has been previously reported [57]. As the efficacy of immune checkpoint blockade is dependent on tumor-infiltrating immune cells and tumor-specific T cell responses [58], increased infiltration of TC-1/dCD80-1-induced tumors by immune cells might contribute to the sensitivity of these tumors to anti-CTLA-4 therapy.…”

Section: Discussionmentioning

confidence: 78%

CD80 Expression on Tumor Cells Alters Tumor Microenvironment and Efficacy of Cancer Immunotherapy by CTLA-4 Blockade

Vackova

Poláková

Johari

et al. 2021

Cancers

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Cluster of differentiation (CD) 80 is mainly expressed in immune cells but can also be found in several types of cancer cells. This molecule may either activate or inhibit immune reactions. Here, we determined the immunosuppressive role of CD80 in the tumor microenvironment by CRISPR/Cas9-mediated deactivation of the corresponding gene in the mouse oncogenic TC-1 cell line. The tumor cells with deactivated CD80 (TC-1/dCD80-1) were more immunogenic than parental cells and induced tumors that gained sensitivity to cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockade, as compared with the TC-1 cells. In vivo depletion experiments showed that the deactivation of CD80 switched the pro-tumorigenic effect of macrophages observed in TC-1-induced tumors into an anti-tumorigenic effect in TC-1/dCD80-1 tumors and induced the pro-tumorigenic activity of CD4+ cells. Moreover, the frequency of lymphoid and myeloid cells and the CTLA-4 expression by T helper (Th)17 cells were increased in TC-1/dCD80-1- compared with that in the TC-1-induced tumors. CTLA-4 blockade downregulated the frequencies of most immune cell types and upregulated the frequency of M2 macrophages in the TC-1 tumors, while it increased the frequency of lymphoid cells in TC-1/dCD80-1-induced tumors. Furthermore, the anti-CTLA-4 therapy enhanced the frequency of CD8+ T cells as well as CD4+ T cells, especially for a Th1 subset. Regulatory T cells (Treg) formed the most abundant CD4+ T cell subset in untreated tumors. The anti-CTLA-4 treatment downregulated the frequency of Treg cells with limited immunosuppressive potential in the TC-1 tumors, whereas it enriched this type of Treg cells and decreased the Treg cells with high immunosuppressive potential in TC-1/dCD80-1-induced tumors. The immunosuppressive role of tumor-cell-expressed CD80 should be considered in research into biomarkers for the prediction of cancer patients’ sensitivity to immune checkpoint inhibitors and for the development of a tumor-cell-specific CD80 blockade.

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Section: Discussionmentioning

confidence: 78%

CD80 Expression on Tumor Cells Alters Tumor Microenvironment and Efficacy of Cancer Immunotherapy by CTLA-4 Blockade

Vackova

Poláková

Johari

et al. 2021

Cancers

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“…We focused our analyses on T, B and NK cells as important lymphocyte effector subsets in cancer. Expression of immune-modulatory molecules by myeloid cells can however be of similar relevance and may also show cancer-type dependent differences in expression patterns, which merit further investigation 57 , 58 . We selected druggable immune-regulatory molecules and additional pathways may be of similar importance.…”

Section: Discussionmentioning

confidence: 99%

Cancer-specific immune evasion and substantial heterogeneity within cancer types provide evidence for personalized immunotherapy

et al. 2021

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The immune response against cancer is orchestrated by various parameters and site-dependent specificities have been poorly investigated. In our analyses of ten different cancer types, we describe elevated infiltration by regulatory T cells as the most common feature, while other lymphocyte subsets and also expression of immune-regulatory molecules on tumor-infiltrating lymphocytes showed site-specific variation. Multiparametric analyses of these data identified similarities of renal and liver or lung with head and neck cancer. Co-expression of immune-inhibitory ligands on tumor cells was most frequent in colorectal, lung and ovarian cancer. Genes related to antigen presentation were frequently dysregulated in liver and lung cancer. Expression of co-inhibitory molecules on tumor-infiltrating T cells accumulated in advanced stages while T-cell abundance was related to enhanced expression of genes related to antigen presentation. Our results promote evaluation of cancer-specific or even personalized immunotherapeutic combinations to overcome primary or secondary resistance as major limitation of immune-checkpoint inhibition.

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“…Targeting Monocytes, Neutrophils, or Macrophages Does Not Sensitize pMMR CRC Liver Metastases to ICB Therapy. Potential inhibitory components to ICB efficacy include myeloid cells such as monocytes, neutrophils, and macrophages, which can promote cancer progression and limit the efficacy of treatments (33)(34)(35). For example, Ly-6C + monocytes in tumors can be immunosuppressive and limit the efficacy of anti-PD1…”

Section: Orthotopic Liver Metastasis Mouse Models Of Pmmr Crc Resist Icbmentioning

confidence: 99%

Dendritic cell paucity in mismatch repair–proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy

Gomes‐Santos

Aoki

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair–proficient (pMMR) CRCs make up about 95% of metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models of orthotopic pMMR CRC liver metastasis accurately recapitulate the inefficacy of ICB therapy in patients, whereas the same pMMR CRC tumors are sensitive to ICB therapy when grown subcutaneously. To reveal local, nonmalignant components that determine CRC sensitivity to treatment, we compared the microenvironments of pMMR CRC cells grown as liver metastases and subcutaneous tumors. We found a paucity of both activated T cells and dendritic cells in ICB-treated orthotopic liver metastases, when compared with their subcutaneous tumor counterparts. Furthermore, treatment with Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 ligand (Flt3L) plus ICB therapy increased dendritic cell infiltration into pMMR CRC liver metastases and improved mouse survival. Lastly, we show that human CRC liver metastases and microsatellite stable (MSS) primary CRC have a similar paucity of T cells and dendritic cells. These studies indicate that orthotopic tumor models, but not subcutaneous models, should be used to guide human clinical trials. Our findings also posit dendritic cells as antitumor components that can increase the efficacy of immunotherapies against pMMR CRC.

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Rethinking immune checkpoint blockade: ‘Beyond the T cell’

Cited by 99 publications

References 96 publications

CD80 Expression on Tumor Cells Alters Tumor Microenvironment and Efficacy of Cancer Immunotherapy by CTLA-4 Blockade

CD80 Expression on Tumor Cells Alters Tumor Microenvironment and Efficacy of Cancer Immunotherapy by CTLA-4 Blockade

Cancer-specific immune evasion and substantial heterogeneity within cancer types provide evidence for personalized immunotherapy

Dendritic cell paucity in mismatch repair–proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy

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