Peripheral myeloid-derived suppressor and T regulatory PD-1 positive cells predict response to neoadjuvant short-course radiotherapy in rectal cancer patients

Napolitano, Maria; D’Alterio, Crescenzo; Cardone, E.; Trotta, Anna Maria; Pecori, Biagio; Rega, Daniela; Pace, Ugo; Scala, D.; Scognamiglio, Giosuè; Tatangelo, Fabiana; Cacciapuoti, Carmela; Pacelli, Roberto; Delrio, Paolo; Scala, Stefania

doi:10.18632/oncotarget.3014

Cited by 52 publications

(38 citation statements)

References 44 publications

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“…Chemotherapeutics or radiotherapy is known to trigger immunogenic cell death (Apetoh et al ., ; Welsh et al ., ). Recent report indicated that radiotherapy could induce the increase in PD1 + Tregs (Napolitano et al ., ). In the present study, we found that TIM3 expression in HNSCC postradiotherapy and HNSCC post‐TPF chemotherapy was significantly higher than that in primary HNSCC, which indicates that TPF chemotherapy and radiotherapy induce the up‐regulation of TIM3.…”

Section: Discussionmentioning

confidence: 97%

T‐cell immunoglobulin mucin 3 blockade drives an antitumor immune response in head and neck cancer

Liu

Mao

et al. 2017

Molecular Oncology

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T‐cell immunoglobulin mucin 3 (TIM3) contributes to immune suppression during progression of many cancers, but the precise role of TIM3 in head and neck squamous cell carcinoma (HNSCC) is not clearly understood. In this study, we report that TIM3 expression was significantly up‐regulated in patients with HNSCC and associated with lymph node metastasis. Additionally, TIM3 expression was increased in patients with recurrent HNSCC and patients with preradiotherapy or prechemotherapy. We also characterized CD8+ T cells and CD11b+ CD33+ myeloid‐derived suppressor cells (MDSCs) in human HNSCC, and found that their expression was positively correlated with TIM3 expression. To determine the underlying mechanism of TIM3 in immune response during HNSCC progression, we utilized the Tgfbr1/Pten 2cKO HNSCC mouse model with TIM3 overexpression. Treatment with anti‐TIM3 monoclonal antibody effectively suppressed tumor growth through restoring effector T‐cell function by targeting CD4+ TIM3+ cells and CD8+ TIM3+ cells and decreasing MDSCs. Our findings demonstrate TIM3 expression in patients with HNSCC and suggest anti‐TIM3 immunotherapy as a novel therapeutic approach for effective treatment of HNSCC.

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Section: Discussionmentioning

confidence: 97%

T‐cell immunoglobulin mucin 3 blockade drives an antitumor immune response in head and neck cancer

Liu

Mao

et al. 2017

Molecular Oncology

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“…14,20 CRT also induces systemic immune changes, including reductions in circulating Tregs and myeloid-derived suppressor cells. 21 This immunomodulation may account for the reported abscopal effects on distant metastases after RT to the primary tumor, potentially mediated by cross-priming of T cells following tumor cell death. 12,18,19 Our results are consistent with previous reports of association between changes in Tregs and treatment response.…”

Section: Discussionmentioning

confidence: 99%

Potential immune priming of the tumor microenvironment with FOLFOX chemotherapy in locally advanced rectal cancer

et al. 2018

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Strategies to enhance tumor immunogenicity may expand the role of immunotherapy beyond the mismatch repair-deficient subtype. In this pilot study, biopsies were performed at baseline and after four cycles of FOLFOX in eight patients receiving neoadjuvant chemotherapy for stage II/III locally advanced rectal cancer. Immunostaining was performed for T cell subsets (CD3+, CD8+, CD45RO+); macrophages (CD163+); T regulatory cells (FOXP3+); and expression of MHC class I, PD-1 and PD-L1. Changes in cell number or intensity were quantified and correlated with treatment response. Pretreatment patterns of immune infiltrates were mixed and did not correlate with treatment response. Posttreatment increases in T cell infiltrates (CD3+, CD8+ and CD45RO+) and MHC-I expression were observed in five patients. CD163+ cell numbers increased in four patients. FOXP3+ cell numbers increased in two patients, decreased in two other patients and remained unchanged in three patients. PD-1 scores increased in seven patients, and PD-L1 scores increased in four patients. Changes in tumor T cell responses did not correlate with treatment response. Changes in FOXP3+ cells were associated with treatment response in some patients: two patients with increases in FOXP3+ cells had poor responses, whereas the patient with the greatest reduction in FOXP3+ cells had a complete response. The patient with a complete clinical response had a much higher increase in MHC-I expression than other patients. These results suggest that chemotherapy can increase immune activity in the tumor microenvironment and could potentially be utilized to prime immune responses prior to immunomodulatory treatments.

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“…Increased levels of HLA-DR low/ neg CD14 + MDSCs detected in the circulation of patients with melanoma [21], HCC [9,22], rectal cancer [23] and prostate cancer [24] correlated with poor prognosis; furthermore, a reciprocal relationship between Tregs and MDSCs has been demonstrated in HCC and prostate cancer patients [9,24,25]. In contrast, an inverse correlation between the frequency of MDSCs and presence of functional antigen-specific T cells found in melanoma patients and breast cancer patients highlights the potent immunosuppressive role of MDSCs in cancer [11,21].…”

Section: Role Of Mdscs In Suppression Of Anti-tumor Immunitymentioning

confidence: 99%

High immunosuppressive burden in cancer patients: a major hurdle for cancer immunotherapy

Kalathil

Thanavala

2016

Cancer Immunol Immunother

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A bottleneck for immunotherapy of cancer is the immunosuppressive microenvironment in which the tumor cells are located. Regardless of the fact that large numbers of tumor-specific T cells can be generated in patients by active immunization or adoptive transfer, these T cells do not readily translate to tumor cell killing in vivo. The immune regulatory mechanism which prevents autoimmunity may be harnessed by tumor cells for the evasion of immune destruction. Regulatory T cells, myeloid-derived suppressor cells, inhibitory cytokines and immune checkpoint receptors are the major components of the immune system acting in concert to cause the subversion of anti-tumor immunity in the tumor microenvironment. This redundant immunosuppressive network may pose an impediment to efficacious immunotherapy, thus facilitating tumor progression. Cancer progression clearly documents the failure of immune control over relentless growth of tumor cells. Detailed knowledge of each of these factors responsible for creating an immunosuppressive shield to protect tumor cells from immune destruction is essential for the development of novel immune based therapeutic interventions of cancer. Multi-pronged targeted depletion of these suppressor cells may restore production of granzyme B by CD8+ T cells and increase the number of IFN-γ producing CD4+ T cells.

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Peripheral myeloid-derived suppressor and T regulatory PD-1 positive cells predict response to neoadjuvant short-course radiotherapy in rectal cancer patients

Cited by 52 publications

References 44 publications

T‐cell immunoglobulin mucin 3 blockade drives an antitumor immune response in head and neck cancer

T‐cell immunoglobulin mucin 3 blockade drives an antitumor immune response in head and neck cancer

Potential immune priming of the tumor microenvironment with FOLFOX chemotherapy in locally advanced rectal cancer

High immunosuppressive burden in cancer patients: a major hurdle for cancer immunotherapy

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