Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery

Predina, Jarrod D.; Eruslanov, Evgeniy; Judy, Brendan F.; Kapoor, Veena; Cheng, Guanjun; Wang, Liang-Chuan; Sun, Jing; Moon, Edmund K.; Fridlender, Zvi G.; Albelda, Steven Μ.; Singhal, Sunil

doi:10.1073/pnas.1211850110

Cited by 168 publications

(154 citation statements)

References 31 publications

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“…To do so, we obtained pleural effusion cells from patients with stage IV NSCLC to check the mRNA levels of IRF5 and M-CSF in EpCAM þ epithelial cells. We also analyzed total numbers of CSF1R-positive macrophages in NSCLC tumors, which have been known as tumorigenic and immunosuppressive subsets in human cancers (20,21). We found that mRNA levels of IRF5 were highly correlated with those of M-CSF in tumor tissues in patients with NSCLC (Fig.…”

Section: Clinical Significance Of Irf5-m-csf Pathwaysmentioning

confidence: 90%

Cancer Stem-like Cells Derived from Chemoresistant Tumors Have a Unique Capacity to Prime Tumorigenic Myeloid Cells

et al. 2014

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Resistance to anticancer therapeutics greatly affects the phenotypic and functional properties of tumor cells, but how chemoresistance contributes to the tumorigenic activities of cancer stem-like cells remains unclear. In this study, we found that a characteristic of cancer stem-like cells from chemoresistant tumors (CSC-R) is the ability to produce a variety of proinflammatory cytokines and to generate M2-like immunoregulatory myeloid cells from CD14 þ monocytes. Furthermore, we identified the IFN-regulated transcription factor IRF5 as a CSC-Rspecific factor critical for promoting M-CSF production and generating tumorigenic myeloid cells. Importantly, myeloid cells primed with IRF5 þ CSC-R facilitate the tumorigenic and stem cell activities of bulk tumors.Importantly, the activation of IRF5/M-CSF pathways in tumor cells were correlated with the number of tumorassociated CSF1 receptor þ M2 macrophages in patients with non-small lung cancer. Collectively, our findings show how chemoresistance affects the properties of CSCs in their niche microenvironments. Cancer Res; 74(10); 2698-709. Ó2014 AACR.

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Section: Clinical Significance Of Irf5-m-csf Pathwaysmentioning

confidence: 90%

Cancer Stem-like Cells Derived from Chemoresistant Tumors Have a Unique Capacity to Prime Tumorigenic Myeloid Cells

et al. 2014

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“…Combination treatment with the anti-CD4 mAb and various immune checkpoint mAbs, particularly anti-PD-1 and anti-PD-L1 mAbs, revealed striking synergy in suppressing tumor growth and prolonging survival. Several previous reports have described antitumor activity of anti-CD4 mAb treatment in solid tumor models in C57BL/6 mice, including subcutaneous tumors induced by inoculation with B16 melanoma cells (9,11,12), recurrent TC1 lung cancer cells (30), or embryo cells expressing the adenovirus-derived E1A protein (10). Although the efficacy of immunotherapy in mouse tumor anti-CD4, anti-PD-L1, anti-PD-1 or anti-CD8 mAbs or a combination of these according to the treatment schedule shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Robust Antitumor Effects of Combined Anti–CD4-Depleting Antibody and Anti–PD-1/PD-L1 Immune Checkpoint Antibody Treatment in Mice

Ueha

Yokochi

Ishiwata

et al. 2015

Cancer Immunology Research

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Depletion of CD4þ cells in tumor-bearing mice has strong antitumor effects. However, the mechanisms underlying these effects and the therapeutic benefits of CD4 þ cell depletion relative to other immunotherapies have not been fully evaluated. Here, we investigated the antitumor effects of an anti-CD4-depleting mAb as a monotherapy or in combination with immune checkpoint mAbs. In B16F10, Colon 26, or Lewis lung carcinoma subcutaneous tumor models, administration of the anti-CD4 mAb alone had strong antitumor effects that were superior to those elicited by CD25 þ Treg depletion or other immune checkpoint mAbs, and which were completely reversed by CD8 þ cell depletion. CD4 þ cell depletion led to the proliferation of tumor-specific CD8 þ T cells in the draining lymph node and increased infiltration of PD-1into the tumor, with a shift toward type I immunity within the tumor. Combination treatment with the anti-CD4 mAb and immune checkpoint mAbs, particularly anti-PD-1 or anti-PD-L1 mAbs, synergistically suppressed tumor growth and greatly prolonged survival. To our knowledge, this work represents the first report of robust synergy between anti-CD4 and anti-PD-1 or anti-PD-L1 mAb therapies.

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“…Five micrometer-thick sections from tissue biopsies obtained during the surgery were mounted with a glycerin-based mounting media and frozen tumor sections were prepared as previously described. 29 The samples were examined using an Olympus ® IX51 fluorescent microscope equipped with an ICG specific filter set (Chroma ® 49030). Fluorescence images were acquired using a PixeLink ® NIR CCD camera (PL-B741EU).…”

Section: Histopathology and Fluorescence Microscopymentioning

confidence: 99%

Intraoperative near-infrared fluorescence imaging and spectroscopy identifies residual tumor cells in wounds

et al. 2015

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Abstract. Surgery is the most effective method to cure patients with solid tumors, and 50% of all cancer patients undergo resection. Local recurrences are due to tumor cells remaining in the wound, thus we explore near-infrared (NIR) fluorescence spectroscopy and imaging to identify residual cancer cells after surgery. Fifteen canines and two human patients with spontaneously occurring sarcomas underwent intraoperative imaging. During the operation, the wounds were interrogated with NIR fluorescence imaging and spectroscopy. NIR monitoring identified the presence or absence of residual tumor cells after surgery in 14∕15 canines with a mean fluorescence signal-to-background ratio (SBR) of ∼16. Ten animals showed no residual tumor cells in the wound bed (mean SBR < 2, P < 0.001). None had a local recurrence at >1-year follow-up. In five animals, the mean SBR of the wound was >15, and histopathology confirmed tumor cells in the postsurgical wound in four/five canines. In the human pilot study, neither patient had residual tumor cells in the wound bed, and both remain disease free at >1.5-year follow up. Intraoperative NIR fluorescence imaging and spectroscopy identifies residual tumor cells in surgical wounds. These observations suggest that NIR imaging techniques may improve tumor resection during cancer operations.

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Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery

Cited by 168 publications

References 31 publications

Cancer Stem-like Cells Derived from Chemoresistant Tumors Have a Unique Capacity to Prime Tumorigenic Myeloid Cells

Cancer Stem-like Cells Derived from Chemoresistant Tumors Have a Unique Capacity to Prime Tumorigenic Myeloid Cells

Robust Antitumor Effects of Combined Anti–CD4-Depleting Antibody and Anti–PD-1/PD-L1 Immune Checkpoint Antibody Treatment in Mice

Intraoperative near-infrared fluorescence imaging and spectroscopy identifies residual tumor cells in wounds

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