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Batf3+ DCs and type I IFN are critical for the efficacy of neoadjuvant cancer immunotherapy.

ABSTRACT: New clinical trials are now evaluating the efficacy of neoadjuvant immunotherapy in the context of primary tumor surgery. Using the orthotopic 4T1.2 mouse model of spontaneously metastatic mammary cancer, we have shown that neoadjuvant immunotherapy and surgery was superior in the generation of tumor-specific CD8+ T cells and eradication of lethal metastases compared to surgery followed by adjuvant immunotherapy. However, the importance of host Batf3 and type I interferon (IFN) for long-term survival of mice following neoadjuvant immunotherapy is unknown. Here we demonstrated that loss of Batf3+ DCs or type I IFN receptor blockade in 4T1.2 tumor-bearing mice treated with neoadjuvant anti-PD-1+anti-CD137 immunotherapy reduced long-term survival with a corresponding reduction in tumor-specific CD8+ T cells producing effector cytokines in the primary tumor and in the periphery. Interestingly, we found all high-risk stage III melanoma patients relapsing after adjuvant or neoadjuvant ipilimumab+nivolumab within the OpACIN trial (NCT02437279) displayed low expression of Batf3+ DC-associated genes in pre-treatment tumor biopsies. Further focus should now be placed on validating the requirement of an intratumoral Batf3+ DC gene signature for response to neoadjuvant immunotherapy.

SUBMITTER: Liu J

PROVIDER: S-EPMC6343771 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Batf3<sup>+</sup> DCs and type I IFN are critical for the efficacy of neoadjuvant cancer immunotherapy.

Liu Jing J Rozeman Elisa A EA O'Donnell Jake S JS Allen Stacey S Fanchi Lorenzo L Smyth Mark J MJ Blank Christian U CU Teng Michele W L MWL

Oncoimmunology 20181122 2

New clinical trials are now evaluating the efficacy of neoadjuvant immunotherapy in the context of primary tumor surgery. Using the orthotopic 4T1.2 mouse model of spontaneously metastatic mammary cancer, we have shown that neoadjuvant immunotherapy and surgery was superior in the generation of tumor-specific CD8<sup>+</sup> T cells and eradication of lethal metastases compared to surgery followed by adjuvant immunotherapy. However, the importance of host Batf3 and type I interferon (IFN) for lo ...[more]

PMID: 30713806

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Project description:Graft-versus-host disease (GvHD) remains the second leading cause of death in allogeneic hematopoietic stem cell transplantation recipients, highlighting the need for improved preventative strategies. Our laboratory has previously demonstrated in an experimental bone marrow transplantation (BMT) model that bendamustine combined with total body irradiation (BEN+TBI) is a safer alternative to cyclophosphamide with TBI (CY+TBI). The biological mechanisms of action of BEN have not been fully elucidated and likely involve multiple cell populations. Host dendritic cells (DCs) can prime naïve donor T-cells immediately following transplantation, making host DCs critical for the initiation phase of GvHD. We hypothesized that BEN+TBI conditioning favorably alters host DC composition to reduce GvHD. We demonstrate that host DCs treated with BEN+TBI induce less allogeneic T-cell proliferation than those conditioned with CY+TBI. We further show that BEN+TBI conditioning results in greater total numbers of all host DC subsets but with a more favorable composition compared to CY+TBI with significantly larger proportions of type 1 conventional DCs (cDC1), a highly regulatory DC subset capable of suppressing GvHD. Our studies using recipient Batf3 KO mice indicate that CD8?+ cDC1s are largely dispensable for the reduced GvHD following BEN+TBI conditioning. We found a higher frequency of host pre-cDC1s with BEN+TBI conditioning in both wild-type (WT) and Batf3 KO mice, which was inversely associated with GvHD. Additionally, we observed that BEN treatment results in greater expression of Flt3 receptor (CD135) on host DCs compared to CY, potentially contributing to the skewing of host DCs toward cDC1s. Further, BEN+TBI conditioning results in host cDCs with greater expression of PIR-B, an inhibitory receptor capable of preventing lethal GvHD. We conclude that BEN+TBI is a safer alternative to CY+TBI, resulting in a greater frequency of host pre-cDC1s and limiting GvHD.

Project description:BackgroundImmune checkpoint inhibitors are increasingly used in neoadjuvant therapy for locally advanced gastric cancer. However, the effect of body composition on the efficacy of neoadjuvant therapy has not been reported.MethodsThe computed tomography (CT) images and clinicopathological data of 101 patients with locally advanced gastric cancer who received neoadjuvant chemotherapy combined with immunotherapy (NCI) from 2019 to 2021 were collected. The CT image of L3 vertebral body section was selected, and the body composition before and after the neoadjuvant treatment was calculated using the SliceOmatic software, mainly including skeletal muscle index (SMI), subcutaneous adipose index (SAI), and visceral adipose index (VAI). The relationship between body composition and the efficacy and adverse events of NCI was analyzed.ResultsOf the 101 patients, 81 with evaluable data were included in the analysis. Of the included patients, 77.8% were male; the median age of all the patients was 62 years, and the median neoadjuvant therapy cycle was three. After the neoadjuvant therapy, 62.9% of the tumors were in remission (residual tumor cells ≤ 50%), and 37.1% of the tumors had no remission (residual tumor cells>50%). Moreover, 61.7% of the patients had treatment-related adverse events (TRAEs), and 18.5% had immune-related adverse events (irAEs). After neoadjuvant therapy, the body mass index (from 23 to 22.6 cm2/m2, p=0.042), SAI (from 34.7 to 32.9 cm2/m2, p=0.01) and VAI (from 32.4 to 26.8 cm2/m2, p=0.005) were significantly lower than those before treatment, while the SMI had no significant change (44.7 vs 42.5 cm2/m2, p=0.278). The multivariate logistics regression analysis revealed that low SMI (odds ratio [OR]: 3.23,95% confidence interval [CI]: 1.06-9.81, p=0.047), SMI attenuation (△SMI) ≥ 1.8(OR: 1.45,95%CI: 1.20-3.48, p=0.048), and clinical node positivity (OR: 6.99,95%CI: 2.35-20.82, p=0.001) were independent risk factors for non-remission. Additionally, high SAI is an independent risk factor for irAEs (OR: 14, 95%CI: 1.73-112.7, p=0.013).ConclusionLow SMI and △SMI≥1.8 are independent risk factors for poor tumor regression in patients with advanced gastric cancer receiving NCI. Patients with a high SAI are more likely to develop irAEs.

Project description:Background and objectiveImmune checkpoint inhibitors and immunotherapy have been shown to improve survival rates, especially in non-small cell lung cancer (NSCLC) patients. More recently, several trials have evaluated the clinical roles of immunotherapy as neoadjuvant settings for NSCLC. There trials suggested that neoadjuvant immunotherapy may effectively reduce the risk of the local recurrence and metastasis of cancer, and significantly improved overall survival and cure rates. Here we conducted a review to summarize the possible mechanism, clinical development, and research progress of neoadjuvant immunotherapy in NSCLC.MethodsRelevant articles for this review were retrieved from Google Scholar, Clinicaltrials.gov., and PubMed using the terms "non-small-cell lung cancer", "NSCLC", "neoadjuvant", "immunotherapy", "immune checkpoint inhibitors", "mechanisms", and "toxicity". The primary focus was placed on clinical studies and conference abstracts measuring the safety and efficacy of neoadjuvant immunotherapy in NSCLC until May 2022.Key content and findingsAfter reviewing the preclinical and clinical trial, the preclinical study showed that neoadjuvant immune checkpoint inhibitor promotes antitumor immunity through the enhancement of T cell effector function and the induction of long-term memory. The initial results of preliminary early-phase trials suggested that neoadjuvant immunotherapy is a promising therapeutic strategy for resectable NSCLC patients, with long-term response and modest toxicity, many of these regimens are currently being evaluated by randomized phase III trials. In addition, the major pathologic response of neoadjuvant immunotherapy ranged up to 45% in these studies when used alone, and up to around 83-86% when used in combination with chemotherapy, therefore it has been seen as a rather potent tumor debulking agent.ConclusionsNeoadjuvant immunotherapy has been shown to be a novel integral component of NSCLC care. However, there are also several research questions that requires further investigation, such as the side effects, the optimally treated patients, and the time of preoperative immunotherapy.

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Batf3+ DCs and type I IFN are critical for the efficacy of neoadjuvant cancer immunotherapy.

Publications

Batf3<sup>+</sup> DCs and type I IFN are critical for the efficacy of neoadjuvant cancer immunotherapy.

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