The Anatomical Location Shapes the Immune Infiltrate in Tumors of Same Etiology and Affects Survival

Santegoets, Saskia J.; Ham, Vanessa J. van; Ehsan, Ilina; Charoentong, Pornpimol; Duurland, Chantal L.; Unen, Vincent van; Höllt, Thomas; Velden, Lilly–Ann van der; Egmond, Sylvia L. van; Kortekaas, Kim E.; Steenwijk, Peggy J. de Vos van; Poelgeest, Mariëtte I.E. van; Welters, Marij J.P.; Burg, Sjoerd H. van der

doi:10.1158/1078-0432.ccr-18-1749

Cited by 47 publications

(63 citation statements)

References 45 publications

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“…Within the adaptive compartment, we found dominant, tumour tissue-specific CD8 + and CD4 + T cell populations that displayed a highly similar activated tissue-resident phenotype. Such CD8 + T cell populations have been described in ovarian cancer,44 45 lung cancer46 and recently in melanoma,47 cervical carcinoma48 and CRC,22 23 and their presence was associated with an improved clinical prognosis. Single-cell RNA-sequencing revealed that CD8 + T cells in colorectal tumours showed a cytotoxic profile, indicative of potential antitumour reactivity.…”

Section: Discussionmentioning

confidence: 90%

High-dimensional cytometric analysis of colorectal cancer reveals novel mediators of antitumour immunity

Vries

Unen

Ijsselsteijn

et al. 2019

Gut

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ObjectiveA comprehensive understanding of anticancer immune responses is paramount for the optimal application and development of cancer immunotherapies. We unravelled local and systemic immune profiles in patients with colorectal cancer (CRC) by high-dimensional analysis to provide an unbiased characterisation of the immune contexture of CRC.DesignThirty-six immune cell markers were simultaneously assessed at the single-cell level by mass cytometry in 35 CRC tissues, 26 tumour-associated lymph nodes, 17 colorectal healthy mucosa and 19 peripheral blood samples from 31 patients with CRC. Additionally, functional, transcriptional and spatial analyses of tumour-infiltrating lymphocytes were performed by flow cytometry, single-cell RNA-sequencing and multispectral immunofluorescence.ResultsWe discovered that a previously unappreciated innate lymphocyte population (Lin–CD7+CD127–CD56+CD45RO+) was enriched in CRC tissues and displayed cytotoxic activity. This subset demonstrated a tissue-resident (CD103+CD69+) phenotype and was most abundant in immunogenic mismatch repair (MMR)-deficient CRCs. Their presence in tumours was correlated with the infiltration of tumour-resident cytotoxic, helper and γδ T cells with highly similar activated (HLA-DR+CD38+PD-1+) phenotypes. Remarkably, activated γδ T cells were almost exclusively found in MMR-deficient cancers. Non-activated counterparts of tumour-resident cytotoxic and γδ T cells were present in CRC and healthy mucosa tissues, but not in lymph nodes, with the exception of tumour-positive lymph nodes.ConclusionThis work provides a blueprint for the understanding of the heterogeneous and intricate immune landscape of CRC, including the identification of previously unappreciated immune cell subsets. The concomitant presence of tumour-resident innate and adaptive immune cell populations suggests a multitargeted exploitation of their antitumour properties in a therapeutic setting.

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Section: Discussionmentioning

confidence: 90%

High-dimensional cytometric analysis of colorectal cancer reveals novel mediators of antitumour immunity

Vries

Unen

Ijsselsteijn

et al. 2019

Gut

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“…Mass cytometry (CyTOF) staining and acquisition was performed as generally described. 13 In short, single-cell suspensions of TC-1 tumors were purified by Percoll gradient to remove aggregates and debris, stained with 37 mouse immune markers, and acquired on a Helios mass cytometer (Fluidigm Sciences). The metal-conjugated antibodies are listed in online supplementary file 1.…”

Section: Mass Cytometry and Data Analysismentioning

confidence: 99%

Lack of myeloid cell infiltration as an acquired resistance strategy to immunotherapy

Nejad

Labrie

Abdulrahman

et al. 2020

J Immunother Cancer

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BackgroundImmunotherapy of cancer is successful but tumor regression often is incomplete and followed by escape. Understanding the mechanisms underlying this acquired resistance will aid the development of more effective treatments.MethodsWe exploited a mouse model where tumor-specific therapeutic vaccination results in tumor regression, followed by local recurrence and resistance. In depth studies on systemic, local and tumor intrinsic changes were performed with flow and mass cytometry, immunohistochemistry, transcriptomics and several perturbation studies with inhibitors or agonistic antibodies in mice. Main findings were recapitulated in vaccinated patients.ResultsFull tumor regression and cure of tumor-bearing mice is dependent on the magnitude of the vaccine-induced T-cell response. Recurrence of tumors did not involve classical immune escape mechanisms, such as antigen-presentation alterations, immune checkpoint expression, resistance to killing or local immune suppression. However, the recurrent tumors displayed a changed transcriptome with alterations in p53, tumor necrosis factor-α and transforming growth factor-β signaling pathways and they became immunologically cold. Remarkably, ex vivo cell-sorted recurrent tumors, directly reinjected in naïve hosts retained their resistance to vaccination despite a strong infiltration with tumor-specific CD8+ T cells, similar to that of vaccine-responsive tumors. The influx of inflammatory mature myeloid effector cells in the resistant tumors, however, was impaired and this turned out to be the underlying mechanisms as restoration of inflammatory myeloid cell infiltration reinstated the sensitivity of these refractory tumors to vaccination. Notably, impaired myeloid cell infiltration after vaccination was also associated with vaccine resistance in patients.ConclusionAn immunotherapy-induced disability of tumor cells to attract innate myeloid effector cells formed a major mechanism underlying immune escape and acquired resistance. These data not only stresses the importance of myeloid effector cells during immunotherapy but also demands for new studies to harness their tumoricidal activities.

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“…Staining was performed as described in detail elsewhere. 29 All reagents were purchased from Fluidigm Sciences unless stated otherwise. In short, samples were incubated with 1 µM Cell-ID intercalator-103Rh to identify dead cells, followed by blockage of mouse Fc-Receptors using anti-mouse CD16/32 (clone 2.4G2, BD Biosciences).…”

Section: Mass Cytometry (Cytof)mentioning

confidence: 99%

Host genetics and tumor environment determine the functional impact of neutrophils in mouse tumor models

Elsas

Kleinovink

Moerland

et al. 2020

J Immunother Cancer

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BackgroundNeutrophils have been reported to have protumor, antitumor or neutral effects in cancer progression. The underlying causes for this functional variability are not clear.MethodsWe studied the role of neutrophils in six different mouse tumor models by intratumoral injection of antimicrobial peptides or vaccination. Changes in systemic and intratumoral immune cells were analyzed by flow-cytometry and mass-cytometry. The role of neutrophils was studied by antibody-mediated neutrophil depletion. Neutrophils from different mouse strains were compared by RNA sequencing.ResultsThe antimicrobial peptide Omiganan reduced the growth of TC-1 tumors in BL/6 mice and CT26 tumors in BALB/c mice. No significant effects were observed in B16F10, MC38 and 4T1 tumors. Growth delay was associated with increased abundance of neutrophils in TC-1 but not CT26 tumors. Systemic neutrophil depletion abrogated Omiganan efficacy in TC-1 but further reduced growth of CT26, indicating that neutrophils were required for the antitumor effect in TC-1 but suppressed tumor control in CT26. Neutrophils were also required for a therapeutic vaccine-induced T-cell mediated control of RMA tumors in BL/6 mice. Clearly, the circulating and intratumoral neutrophils differed in the expression of Ly6G and CD62L, between TC-1 and CT26 and between blood neutrophils of tumor-naïve BL/6 and BALB/c mice. RNA-sequencing revealed that neutrophils from BL/6 mice but not BALB/c mice displayed a robust profile of immune activation, matching their opposing roles in TC-1 and RMA versus CT26.ConclusionsNeutrophil functionality differs strongly between mouse strains and tumor types, with consequences for tumor progression and therapy.

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The Anatomical Location Shapes the Immune Infiltrate in Tumors of Same Etiology and Affects Survival

Cited by 47 publications

References 45 publications

High-dimensional cytometric analysis of colorectal cancer reveals novel mediators of antitumour immunity

High-dimensional cytometric analysis of colorectal cancer reveals novel mediators of antitumour immunity

Lack of myeloid cell infiltration as an acquired resistance strategy to immunotherapy

Host genetics and tumor environment determine the functional impact of neutrophils in mouse tumor models

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