Disruption of evasive immune cell microenvironment in tumors reflects immunity induced by radiation therapy

Filatenkov, Alexander; Baker, Jeanette; Strober, Samuel

doi:10.1080/2162402x.2015.1072673

Cited by 8 publications

(7 citation statements)

References 11 publications

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“…Preclinical data in mice colon cancer models confirm immune responses (e.g. CD8 + T cells infiltrate) to antigenic signals elicited by radiotherapy are also rapid -reaching a maximal response within 8-10 days after irradiation and waning quickly back to baseline levels [95][96][97][98] (Table 2, Fig. 5B).…”

Section: Preclinical Evidence For the Timing Of Immune Response Production Of Neoantigens And The Creation Of Memory Cells?mentioning

confidence: 69%

“…In the third model (Table 2), a major CD8+ T cell infiltrate was observed by day 14 with depletion of MDSCs [97]. Durable remissions from radiation were associated with these reductions in the infiltration of MDSCs, TAMs and Tregs, and an increase in CD8 + T cells [98]. Mice in remission resisted re-challenge with tumour cells, and their T cells transferred this antitumor immunity to adoptive hosts.…”

Section: Preclinical Evidence For the Timing Of Immune Response Production Of Neoantigens And The Creation Of Memory Cells?mentioning

confidence: 95%

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The optimal timing for the interval to surgery after short course preoperative radiotherapy (5 ×5 Gy) in rectal cancer - are we too eager for surgery?

Glynne‐Jones

Hall

Nagtegaal

2020

Cancer Treatment Reviews

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Background:The improved overall survival (OS) after short course preoperative radiotherapy (SCPRT) using 5 × 5 Gy reported in the early rectal cancer trials could not be replicated in subsequent phase III trials. This original survival advantage is attributed to poor quality of surgery and the large differential in local recurrence rates, with and without SCPRT. Immuno-modulation during and after SCPRT and its clinical implications have been poorly investigated. We propose an alternative explanation for this survival benefit in terms of immunological mechanisms induced by SCPRT and the timing of surgery, which may validate the concept of consolidation chemotherapy. Material and methods: We reviewed randomized controlled trials (RCTs) and studies of SCPRT from 1985 to 2019. We aimed to examine the precise timing of surgery in days following SCPRT and identify evidence for immune modulation, neo-antigens and memory cell induction by radiation. Results: Considerable variability is reported in randomised trials for median overall treatment time (OTT) from start of SCPRT to surgery (8-14 days). Only three early trials showed a benefit in terms of OS from SCPRT, although the level of benefit in preventing local recurrence was consistent across all trials. Different patterns of immune effects are observed within days after SCPRT depending on the OTT, but human leukocyte antigen (HLA)-1 expression was not upregulated. Conclusions: SCPRT has a substantial immune-stimulatory potential. The importance of the timing of surgery after SCPRT may have been underestimated. An optimal interval for surgery after 5 × 5 Gy may lead to better outcomes, which is possibly exploited in total neoadjuvant therapy schedules using consolidation chemotherapy. Individual patient meta-analyses from appropriate SCPRT trials examining outcomes for each day and prospective trials are needed to clarify the validity of this hypothesis. The interaction of SCPRT with tumour adaptive immunology, in particular the kinetics and timing, should be examined further.

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Section: Preclinical Evidence For the Timing Of Immune Response Production Of Neoantigens And The Creation Of Memory Cells?mentioning

confidence: 69%

Section: Preclinical Evidence For the Timing Of Immune Response Production Of Neoantigens And The Creation Of Memory Cells?mentioning

confidence: 95%

The optimal timing for the interval to surgery after short course preoperative radiotherapy (5 ×5 Gy) in rectal cancer - are we too eager for surgery?

Glynne‐Jones

Hall

Nagtegaal

2020

Cancer Treatment Reviews

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“…On the other hand, PD1 acts directly on the TME; therefore, blockade of the PD1 axis promotes the activation of T cells that infiltrated the tumor site upon RT intervention [ 193 ]. In line with these observations, pre-clinical in vivo data highlighted a trajectory of immune effects such as reduction in the infiltration of MDSCs, TAMs and Tregs, and an increase in CD8 + T cells alongside the expression of HLA, CEA, MUC-1 and ICAM-1 reaching a peak within 8–15 days after irradiation [ 153 , 194 , 195 ]. Although optimal sequencing of RT and ICIs is not yet determined, these studies suggest that, in order to benefit from the highest levels of CD8 + T cells, anti-PD1 antibodies should be administered together with RT [ 191 ].…”

Section: Combining Radiotherapy With Immune Checkpoint Inhibitorsmentioning

confidence: 70%

Emerging Trends for Radio-Immunotherapy in Rectal Cancer

Corrò

Dutoit

Koessler

2021

Cancers

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Rectal cancer is a heterogeneous disease at the genetic and molecular levels, both aspects having major repercussions on the tumor immune contexture. Whilst microsatellite status and tumor mutational load have been associated with response to immunotherapy, presence of tumor-infiltrating lymphocytes is one of the most powerful prognostic and predictive biomarkers. Yet, the majority of rectal cancers are characterized by microsatellite stability, low tumor mutational burden and poor T cell infiltration. Consequently, these tumors do not respond to immunotherapy and treatment largely relies on radiotherapy alone or in combination with chemotherapy followed by radical surgery. Importantly, pre-clinical and clinical studies suggest that radiotherapy can induce a complete reprograming of the tumor microenvironment, potentially sensitizing it for immune checkpoint inhibition. Nonetheless, growing evidence suggest that this synergistic effect strongly depends on radiotherapy dosing, fractionation and timing. Despite ongoing work, information about the radiotherapy regimen required to yield optimal clinical outcome when combined to checkpoint blockade remains largely unavailable. In this review, we describe the molecular and immune heterogeneity of rectal cancer and outline its prognostic value. In addition, we discuss the effect of radiotherapy on the tumor microenvironment, focusing on the mechanisms and benefits of its combination with immune checkpoint inhibitors.

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“…A study comparing intratumoral infiltration of immunocytes pre- and post-neoadjuvant chemoradiotherapy in rectal cancer specimens demonstrated significant elevation of CD8+ and CD4+ T-cells post-treatment whereas MDSC, Tregs, and expression of co-inhibitory receptors remained stable ( 143 ). Similarly, ablative radiotherapy (1 × 30 Gy) has been shown to increase CD8+ cells and decrease MDSC in the TME of CT26 and MC38 murine tumors, whereas fractionated radiation did not trigger such strong lymphocytic responses ( 144 ).…”

Section: Effect Of Local Radiation On Inflammatory Cellsmentioning

confidence: 99%

Radiation-Induced Transformation of Immunoregulatory Networks in the Tumor Stroma

2018

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The implementation of novel cancer immunotherapies in the form of immune checkpoint blockers represents a major advancement in the treatment of cancer, and has renewed enthusiasm for identifying new ways to induce antitumor immune responses in patients. Despite the proven efficacy of neutralizing antibodies that target immune checkpoints in some refractory cancers, many patients do not experience therapeutic benefit, possibly owing to a lack of antitumor immune recognition, or to the presence of dominant immunosuppressive mechanisms in the tumor microenvironment (TME). Recent developments in this field have revealed that local radiotherapy (RT) can transform tumors into in situ vaccines, and may help to overcome some of the barriers to tumor-specific immune rejection. RT has the potential to ignite tumor immune recognition by generating immunogenic signals and releasing neoantigens, but the multiple immunosuppressive forces in the TME continue to represent important barriers to successful tumor rejection. In this article, we review the radiation-induced changes in the stromal compartments of tumors that could have an impact on tumor immune attack. Since different RT regimens are known to mediate strikingly different effects on the multifarious elements of the tumor stroma, special emphasis is given to different RT schedules, and the time after treatment at which the effects are measured. A better understanding of TME remodeling following specific RT regimens and the window of opportunity offered by RT will enable optimization of the design of novel treatment combinations.

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Disruption of evasive immune cell microenvironment in tumors reflects immunity induced by radiation therapy

Cited by 8 publications

References 11 publications

The optimal timing for the interval to surgery after short course preoperative radiotherapy (5 ×5 Gy) in rectal cancer - are we too eager for surgery?

The optimal timing for the interval to surgery after short course preoperative radiotherapy (5 ×5 Gy) in rectal cancer - are we too eager for surgery?

Emerging Trends for Radio-Immunotherapy in Rectal Cancer

Radiation-Induced Transformation of Immunoregulatory Networks in the Tumor Stroma

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