Body composition as a modulator of response to immunotherapy in lung cancer: time to deal with it

Trestini, Ilaria; Caldart, A.; Dodi, Alessandra; Avancini, Alice; Tregnago, Daniela; Sartori, Giulia; Belluomini, Lorenzo; Milella, Michèle; Pilotto, Sara

doi:10.1016/j.esmoop.2021.100095

Cited by 9 publications

(6 citation statements)

References 25 publications

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“…Thus, high sPD-1 plasma concentration may impair the effectiveness of ICIs by neutralizing the PD-1 inhibitors pembrolizumab and nivolumab, resulting in treatment resistance and consequently a shorter TTF. 45,46 Although this hypothesis is intriguing, it does not explain the better clinical outcomes in overweight melanoma patients showing low sPD-1 levels, compared to normal-weight patients with the same low sPD-1. The link between a metabolic factor and the sPD-1 expression in determining the immunotherapy response could be explained by PD-1-mediated T-cell dysfunction induced by excess adiposity.…”

Section: Discussionmentioning

confidence: 98%

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Prognostic role of soluble PD-1 and BTN2A1 in overweight melanoma patients treated with nivolumab or pembrolizumab: finding the missing links in the symbiotic immune-metabolic interplay

et al. 2023

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Individual response to immune checkpoint inhibitors (ICIs) is currently unpredictable in patients with melanoma. Recent findings highlight a striking improvement in the clinical outcomes of overweight/obese patients treated with ICIs, which seems driven, at least in part, by programmed cell death protein 1 (PD-1)-mediated T-cell dysfunction. A putative role of butyrophilins (BTNs) is under investigation as a novel mechanism of cancer immune evasion and obesity-associated inflammation. This study investigates the role of baseline plasma levels of soluble PD-1 (sPD-1), soluble programmed cell death ligand 1 (sPD-L1), BTN2A1 (sBTN2A1), BTN3A1 (sBTN3A1), along with body mass index (BMI), as predictive biomarkers of immunotherapy response in metastatic melanoma patients treated with nivolumab or pembrolizumab as first-line treatment. In all, 41 patients were included in the study. The baseline plasma level of sPD-1 was significantly lower, and the sBTN2A1 was significantly higher, in long-responder patients to nivolumab or pembrolizumab (median sPD-1: 10.3 ng/ml versus 16.6 ng/ml, p = 0.001; median sBTN2A1: 4.4 ng/ml versus 3.77 ng/ml, p = 0.004). Lower levels of sPD-1 and higher levels of sBTN2A1 were also significantly associated with better overall response rate. Notably, when we further stratified the study cohort using BMI along with sPD-1, patients with BMI ⩾ 25 and sPD-1 < 11.24 ng/ml had longer time to treatment failure after PD-1 inhibitor than other subgroups of patients ( p < 0.001). Circulating sPD-1 and sBTN2A1 detection, along with BMI, could give more insights into the immune-metabolic interactions underlying the benefit observed in overweight/obese patients, improving the use of dynamic, noninvasive, biomarkers for patient selection.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Prognostic role of soluble PD-1 and BTN2A1 in overweight melanoma patients treated with nivolumab or pembrolizumab: finding the missing links in the symbiotic immune-metabolic interplay

et al. 2023

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“…The finding that visceral adipose tissue deposits drive differences in CRS severity is in line with previous reports demonstrating a strong association of VAT with obesityassociated metaflammation and the development of cardiovascular diseases and diabetes 24,25 . The 'obesity paradox', meaning the unexpected inverse relationship between excess adipose tissue and immunotherapy efficacy, has been established for immune checkpoint blockade both in preclinical models and in cancer patients 40,41 . The observed therapeutic benefit in the excess weight population was further enhanced when immune-related adverse events occurred 42 .…”

Section: Discussionmentioning

confidence: 99%

“… 24 , 25 The ‘obesity paradox’, meaning the unexpected inverse relationship between excess adipose tissue and immunotherapy efficacy, has been established for immune checkpoint blockade both in preclinical models and in cancer patients. 40 41 The observed therapeutic benefit in the excess weight population was further enhanced when immune-related adverse events occurred. 42 However, the impact of overweight and obesity on survival and toxicity has been more mixed in the context of BCL in the pre-CAR-T era.…”

Section: Discussionmentioning

confidence: 99%

Increased visceral fat distribution and body composition impact cytokine release syndrome onset and severity after CD19 chimeric antigen receptor T-cell therapy in advanced B-cell malignancies

et al. 2022

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Chimeric antigen receptor T-cell (CAR-T) therapy is associated with a distinct toxicity profile that includes cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS is is characterized by the release of pro-inflammatory cytokines such as interleukin-6 (IL-6) and is closely linked to CAR-T expansion and bystander cells like monocytes/macrophages. In other hyperinflammatory states, obesity contributes to inflammatory cascades and acts as a risk factor for disease severity. We aimed to study the influence of anthropometric and body composition (BC) measurements on CAR-T-related immunotoxicity in 64 patients receiving CD19-directed CAR-T for relapsed/refractory B-cell malignancies. Patients with grade ≥ 2 CRS presented with a significantly higher median BMI, waist circumference, Waist-to-Height Ratio (WtHR) and visceral adipose tissue (VAT). These parameters were also found to be associated with an earlier CRS onset. Other adipose deposits and muscle mass did not differ between patients with CRS 0-1° vs CRS ≥ 2°. Moreover, BC parameters did not influence ICANS severity or onset. In a multivariate binary logistic regression incorporating known risk factors of immunotoxicity, the factors BMI, waist circumference, WtHR and VAT increased the probability of grade ≥ 2 CRS. Receiver operating characteristic (ROC) analyses were utilized to determine optimal discriminatory thresholds for these parameters. Patients above these thresholds displayed markedly increased peak IL-6 levels. Our data imply that increased body composition and VAT in particular represent an additional risk factor for severe and early CRS. These findings carry implications for risk-stratification prior to CD19 CAR-T and may be integrated into established risk models.

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“…The etiological basis of this marked variability in clinical response across individuals remains mostly unknown. Body composition, 3 prior antibiotic treatment, 4 gut microbiota composition, 5 genetic susceptibility to autoimmunity, 6 tumor irradiation, 7 and development of thyroiditis after exposure to ICIs [8][9][10] have all been associated with changes in the clinical response to ICI treatment, but a comprehensive hypothesis to explain these observations is lacking.…”

Section: How This Study Might Affect Research Practice or Policymentioning

confidence: 99%

Preconditioning of the immune system modulates the response of papillary thyroid cancer to immune checkpoint inhibitors

Pani

Yasuda

Rousseau

et al. 2022

J Immunother Cancer

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BackgroundThe response of solid tumors such as papillary thyroid cancer (PTC) to immune checkpoint inhibitors (ICIs) is highly variable. The biological basis of this variability remains unknown.MethodsTo test the hypothesis that preconditioning of the immune system modulates the therapeutic effect of ICIs, we used a murine model where PTC and iodine exacerbated thyroiditis (IET) can be induced in a temporally predictable fashion. A total of 122 mice were divided into 3 experimental groups. In the first one, named concomitant IET and PTC (No.=40), IET, and PTC were induced at the same time; in the second one, named pre-existing IET (No.=44), IET was induced prior to the induction of PTC; in the third one, named no IET (No.=38), only PTC was induced. Following disease induction, mice of each group were treated with anti-PD-1 antibody, anti-lymphocyte activation gene 3 antibody (anti-Lag3), anti-T-cell immunoglobulin and mucin domain 3 antibody (anti-Tim3), or IgG control. Ten weeks after the initial ICI injection, mice were sacrificed to collect the thyroid gland for histological analysis, to quantify the incidence and burden of PTC, and to perform high-throughput single-cell RNA sequencing of infiltrating CD45+cells.ResultsIn the concomitant IET and PTC group, ICI treatment reduced PTC incidence (p=0.002 comparing treatment with any ICI vs control), while it had no effect in the pre-existing IET and no IET groups. Single-cell sequencing of thyroidal CD45+cells showed that the different ICIs tested had both specific and shared effects on all the components of the thyroidal immune cell infiltrate. The shared effect of the tested ICIs was dependent on the presence of pre-existing versus concomitant IET. In the context of concomitant IET, ICI treatment resulted in the modulation of a greater number of pathways related to both innate and adaptive immunity.ConclusionsResponse to ICIs depends on the status of the immune system of the treated individual. Modulation of the immune system should be explored as a tool to improve response to ICIs in patients with PTC or other forms of cancer.

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Body composition as a modulator of response to immunotherapy in lung cancer: time to deal with it

Cited by 9 publications

References 25 publications

Prognostic role of soluble PD-1 and BTN2A1 in overweight melanoma patients treated with nivolumab or pembrolizumab: finding the missing links in the symbiotic immune-metabolic interplay

Prognostic role of soluble PD-1 and BTN2A1 in overweight melanoma patients treated with nivolumab or pembrolizumab: finding the missing links in the symbiotic immune-metabolic interplay

Increased visceral fat distribution and body composition impact cytokine release syndrome onset and severity after CD19 chimeric antigen receptor T-cell therapy in advanced B-cell malignancies

Preconditioning of the immune system modulates the response of papillary thyroid cancer to immune checkpoint inhibitors

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