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

Abstract

Immune checkpoint inhibitors (ICIs), targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1), are increasingly reshaping the therapeutic landscape of lung cancer.1Tan W.L. Jain A. Takano A. et al.Novel therapeutic targets on the horizon for lung cancer.Lancet Oncol. 2016; 17: e347-e362Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar,2Hirsch F.R. Scagliotti G.V. Mulshine J.L. et al.Lung cancer: current therapies and new targeted treatments.Lancet. 2017; 389: 299-311Abstract Full Text Full Text PDF PubMed Scopus (1048) Google Scholar Despite striking successes, only a limited proportion of patients achieve a relevant and long-lasting benefit with such treatments.3Postow M.A. Sidlow R. Hellmann M.D. Immune-related adverse events associated with immune checkpoint blockade.N Engl J Med. 2018; 378: 158-168Crossref PubMed Scopus (1380) Google Scholar Individual patient response to ICI-based therapeutic strategies is currently unpredictable: besides the established (and still debated) role of PD-L1 expression, detection of putative tissue- and blood-based biomarkers (still in their experimental phase of development) is challenging both technologically and economically.4Otoshi T. Nagano T. Tachihara M. et al.Possible biomarkers for cancer immunotherapy.Cancers (Basel). 2019; 11: 935Crossref Scopus (21) Google Scholar Thus, identification of clinical (and ideally modifiable) predictors of ICI efficacy represents a crucial goal in the immunotherapy era. To date, two opposite, potentially modifiable, body composition (BC)-related phenotypes have been suggested to potentially modulate immunotherapy outcomes in lung cancer patients: muscle wasting/sarcopenia and excess adiposity/obesity (Figure 1). Muscle wasting is a prominent BC phenotype in lung cancer patients, which reflects increased protein degradation, reduced protein synthesis or a relative imbalance of the two, due to a complex interplay among cytokines, hormones and other humoral factors, change in energy and substrate metabolism and reduction in nutrient intake or availability, as well as in physical activity.5Trestini I. Gkountakos A. Carbognin L. et al.Muscle derangement and alteration of the nutritional machinery in NSCLC.Crit Rev Oncol Hematol. 2019; 141: 43-53Crossref PubMed Scopus (7) Google Scholar In this regard, recent evidence suggests a potential association between BC and weight loss and immunotherapy efficacy.6Trestini I. Sperduti I. Sposito M. et al.Evaluation of nutritional status in non-small-cell lung cancer: screening, assessment and correlation with treatment outcome.ESMO Open. 2020; 5: e000689Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Clinical data on this topic are quite limited. Recently, a systematic review and meta-analysis concluded that baseline computerized tomography (CT) -assessed depletion of skeletal muscle mass and its onset or worsening during immunotherapy are associated with worse treatment response and shorter long-term efficacy in non-small-cell lung cancer (NSCLC) patients treated with ICIs, identifying sarcopenia as a potential negative predictive biomarker.7Wang J. Cao L. Xu S. Sarcopenia affects clinical efficacy of immune checkpoint inhibitors in non-small cell lung cancer patients: a systematic review and meta-analysis.Int Immunopharmacol. 2020; 88: 106907Crossref PubMed Scopus (6) Google Scholar Among possible explanations for primary resistance to immunotherapy in sarcopenic patients, detrimental effects on the immune system mediated by chronic inflammation, suboptimal drug exposure and higher rates of adverse events and treatment discontinuation have been proposed.8Brocco D. Di Marino P. Grassadonia A. From cachexia to obesity: the role of host metabolism in cancer immunotherapy.Curr Opin Support Palliat Care. 2019; 13: 305-310Crossref PubMed Scopus (7) Google Scholar Skeletal muscle cells may modulate immune response by interacting with immune cells, as non-professional antigen-presenting cells, expressing major histocompatibility complexes I and II and affecting T-cell function.9Afzali A.M. Müntefering T. Wiendl H. et al.Skeletal muscle cells actively shape (auto)immune responses.Autoimmun Rev. 2018; 17: 518-529Crossref PubMed Scopus (20) Google Scholar Additionally, proinflammatory cytokines released as part of the cancer-induced chronic inflammation, a major contributor to muscle breakdown, may also affect immune response, leading to immune escape. In this regard, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which are implicated in the activation of several catabolic pathways, such as protein degradation and decreased synthesis, may promote increased angiogenesis and an immunosuppressive environment, characterized by the expression of immune checkpoints in effector T cells and the recruitment of immune suppressor cells.10Qu X. Tang Y. Hua S. Immunological approaches towards cancer and inflammation: a cross talk.Front Immunol. 2018; 9: 563Crossref PubMed Scopus (117) Google Scholar Interleukin-1β (IL-1β) enhances tumor-infiltrating myeloid-derived suppressor cells (MDSCs), which inhibit T-cell and natural killer (NK) cell functions to promote tumoral growth and play an important role in ICI resistance.11Law A.M.K. Valdes-Mora F. Gallego-Ortega D. Myeloid-derived suppressor cells as a therapeutic target for cancer.Cells. 2020; 9: 561Crossref Scopus (73) Google Scholar MDSCs, in turn, activate Treg lymphocytes, which contribute to the immunosuppressive milieu, especially through the production of interleukin-10 (IL-10) which inhibits CD4+ and CD8+ T-cell function, leading to tumor progression.12Li C. Jiang P. Wei S. et al.Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects.Mol Cancer. 2020; 19: 116Crossref PubMed Scopus (47) Google Scholar Furthermore, M2 macrophages secrete transforming growth factor-β (TGF-β), a tissue-remodeling and potentially tumorigenic factor, which promotes angiogenesis and immunosuppression.13De Guillebon E. Dardenne A. Saldmann A. et al.Beyond the concept of cold and hot tumors for the development of novel predictive biomarkers and the rational design of immunotherapy combination.Int J Cancer. 2020; 147: 1509-1518Crossref PubMed Scopus (12) Google Scholar Such immunosuppressive events, observed in cachectic patients, can lead to immunotherapy resistance.13De Guillebon E. Dardenne A. Saldmann A. et al.Beyond the concept of cold and hot tumors for the development of novel predictive biomarkers and the rational design of immunotherapy combination.Int J Cancer. 2020; 147: 1509-1518Crossref PubMed Scopus (12) Google Scholar Overall, the release of cytokines involved in muscle catabolism and cachexia may also induce systemic inflammation and immunosuppression, associated with worse outcomes in cancer patients treated with immunotherapy.14Laino A.S. Woods D. Vassallo M. et al.Serum interleukin-6 and C-reactive protein are associated with survival in melanoma patients receiving immune checkpoint inhibition.J Immunother Cancer. 2020; 8: e000842Crossref PubMed Scopus (25) Google Scholar On the other hand, recent data showed an unexpected inverse relationship between obesity and the efficacy of ICIs, the so-called ‘obesity paradox,’ both in preclinical models and actual cancer patients.15Murphy W.J. Longo D.L. The surprisingly positive association between obesity and cancer immunotherapy efficacy.J Am Med Assoc. 2019; 321: 1247-1248Crossref Scopus (28) Google Scholar In a large cohort of metastatic NSCLC patients with high PD-L1 expression receiving first-line pembrolizumab, obese patients had a significantly higher overall response rate (ORR), progression-free survival (PFS) and overall survival (OS); such correlation was not observed in the chemotherapy-treated cohort, suggesting that only patients who received immunotherapy had a clinical benefit related to obesity.16Cortellini A. Ricciuti B. Tiseo M. et al.Baseline BMI and BMI variation during first line pembrolizumab in NSCLC patients with a PD-L1 expression ≥ 50%: a multicenter study with external validation.J Immunother Cancer. 2020; 8: e001403Crossref PubMed Scopus (16) Google Scholar This concept becomes even more intriguing considering the relatively recent introduction of combinations of chemotherapy and immunotherapy as a new standard of care for NSCLC,17Gandhi L. Rodríguez-Abreu D. Gadgeel S. et al.Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.N Engl J Med. 2018; 378: 2078-2092Crossref PubMed Scopus (2341) Google Scholar further highlighting the need to clarify the relationship between BC and chemotherapy and/or ICIs. A possible underlying mechanism justifying the benefit observed in obese patients might consist of the immune-suppressed phenotype caused by obesity-related chronic inflammation, characterized by a T-helper 1 (Th1) and T-helper 17 (Th17) dominated environment, an increase of M1-like macrophages18Liu R. Nikolajczyk B.S. Tissue immune cells fuel obesity-associated inflammation in adipose tissue and beyond.Front Immunol. 2019; 10: 1587Crossref PubMed Scopus (56) Google Scholar and T-cell dysfunction and exhaustion, with a consequent increase of PD-1 expression on CD8+ T cells. A recent study demonstrated that these features lead to higher responsiveness to ICIs in obese tumor-bearing mice, data corroborated by the clinical observation of improved outcomes in obese patients affected by a wide range of cancers, without an increase in immune-related adverse events. As reported by the authors, the increase of PD-1 expression and T cells aging could potentially be mediated by leptin through the STAT3 pathway.19Wang Z. Aguilar E.G. Luna J.I. et al.Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade.Nat Med. 2019; 25: 141-151Crossref PubMed Scopus (217) Google Scholar Leptin, whose plasma levels correlate with obesity, is an important inflammatory mediator adipokine, able to promote cytokine release, activate Th17 proliferation, impair NK cytotoxicity when increased and contribute to MDSCs induction.8Brocco D. Di Marino P. Grassadonia A. From cachexia to obesity: the role of host metabolism in cancer immunotherapy.Curr Opin Support Palliat Care. 2019; 13: 305-310Crossref PubMed Scopus (7) Google Scholar Another important adipokine involved is adiponectin, normally reduced during obesity, which has been shown to regulate macrophage proliferation, plasticity and polarization (toward an M2-phenotype), innate-like lymphocyte activity and other innate immune cells functions.20Luo Y. Liu M. Adiponectin: a versatile player of innate immunity.J Mol Cell Biol. 2016; 8: 120-128Crossref PubMed Scopus (84) Google Scholar The definition of the physiological role and impact on immunity of these adipokines may be crucial for the definition of targeted therapeutic strategies. Another key point to be considered is that BC phenotypes may contribute to determining drug pharmacokinetics and predicting drug-related toxicities in cancer patients. In the case of ICIs, the lack of data about their pharmacokinetic profile in patients with high body mass index (BMI) and the use of flat-dose administration further increase the complexity of the correlation between BMI and immunotherapeutic agents.21Giannone G. Ghisoni E. Genta S. et al.Immuno-metabolism and microenvironment in cancer: key players for immunotherapy.Int J Mol Sci. 2020; 21: 4414Crossref Scopus (14) Google Scholar Cachexia has been associated with primary resistance to immunotherapy because of suboptimal drug exposure, and anorexia/cachexia-related metabolic wasting has been hypothesized to accelerate the clearance of circulating antibodies, resulting in worse clinical outcomes.22Turner D.C. Kondic A.G. Anderson K.M. et al.Pembrolizumab exposure-response assessments challenged by association of cancer cachexia and catabolic clearance.Clin Cancer Res. 2018; 24: 5841-5849Crossref PubMed Scopus (73) Google Scholar Intriguingly, the combination of low muscle and high adipose tissue (sarcopenic obesity), an emerging abnormal and occult BC phenotype in oncology, may help identify a subgroup of patients who may actually not gain any benefit from immunotherapy. A recent study among patients with metastatic melanoma receiving ICIs suggests that patients with higher muscle and low or intermediate fat content seem to have better outcomes than those with high fat/low muscle.23Young A.C. Quach H.T. Song H. et al.Impact of body composition on outcomes from anti-PD1 +/- anti-CTLA-4 treatment in melanoma.J Immunother Cancer. 2020; 8: e000821Crossref PubMed Scopus (13) Google Scholar In light of currently available data, we may speculate that, although the balance between muscle and fat mass seems to be crucial, the ‘relative prognostic weight’ of skeletal muscle mass compared with adiposity is likely to be superior. Overall, the evaluation of BC is likely to become crucial in the clinical decision-making process when starting an ICI-based treatment and for effective patient selection and stratification for future clinical trials employing this class of anticancer agents. In this context, CT scans, routinely acquired for cancer diagnosis and staging, represent an easy modality to provide a careful assessment of BC at specific and relevant time-points throughout the entire course of the patient's treatment, across different body weight, and hence BMI, spectra.24Prado C.M. Cushen S.J. Orsso C.E. et al.Sarcopenia and cachexia in the era of obesity: clinical and nutritional impact.Proc Nutr Soc. 2016; 75: 188-198Crossref PubMed Scopus (111) Google Scholar In detail, a single axial CT image for regional BC analysis at the third lumbar vertebra has been described to be associated with the whole BC.25Shen W. Punyanitya M. Wang Z. et al.Total body skeletal muscle and adipose tissue volumes: estimation from a single abdominal cross-sectional image.J Appl Physiol (1985). 2004; 97: 2333-2338Crossref PubMed Scopus (847) Google Scholar Using a commercially available image analysis software, muscle and different adipose tissue deposits can be estimated based on the Hounsfield unit (HU) tissue-specific thresholds.24Prado C.M. Cushen S.J. Orsso C.E. et al.Sarcopenia and cachexia in the era of obesity: clinical and nutritional impact.Proc Nutr Soc. 2016; 75: 188-198Crossref PubMed Scopus (111) Google Scholar The abnormal BC phenotypes are prevalent and often hidden conditions in clinical practice, which may be neglected by the use of ‘standard’ anthropometric measurements such as weight, BMI and weight loss. In the new era of precision medicine, early assessment and monitoring of BC should be routinely carried out in lung cancer patients, despite normal or heavy body weight, since its intrinsic prognostic meaning and, more importantly, in order to offer the patient a tailored therapeutic intervention with the potential of implementing the expected outcome and/or tolerability of available therapies. Baseline and ongoing modifications of circulating cytokines and inflammatory biomarkers along with longitudinal BC detection could give more insights into the mechanisms linking metabolic signatures to immunotherapy response. Moreover, the possibility to explore strategies aimed at optimizing BC (such as tailored nutritional counseling, exercise programs and pharmacological approaches) toward a more immunoresponsive phenotype is extremely intriguing for promoting ICI efficacy and potentially reversing resistance in a proportion of lung cancer patients. None declared.

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